Tangential migration of glutamatergic neurons and cortical patterning during development: Lessons from Cajal-Retzius cells.

Tangential Migration of Glutamatergic Neurons and Cortical Patterning during Development: Lessons from Cajal-Retzius Cells Melissa Barber,1,2 Alessandra Pierani1 1

Paris Diderot, Sorbonne Cite , Paris, France Institut Jacques-Monod, CNRS, Universite

2

Department of Cell and Developmental Biology, University College London, WC1E 6BT, United Kingdom

Received 11 September 2015; revised 12 November 2015; accepted 13 November 2015

ABSTRACT: Tangential migration is a mode of cell movement, which in the developing cerebral cortex, is defined by displacement parallel to the ventricular surface and orthogonal to the radial glial fibers. This mode of long-range migration is a strategy by which distinct neuronal classes generated from spatially and molecularly distinct origins can integrate to form appropriate neural circuits within the cortical plate. While it was previously believed that only GABAergic cortical interneurons migrate tangentially from their origins in the subpallial ganglionic eminences to integrate in the cortical plate, it is now known that transient populations of glutamatergic neurons also adopt this mode of migration. These include Cajal-Retzius cells (CRs), subplate neurons (SPs), and cortical plate transient neurons (CPTs), which have crucial roles in orchestrating the radial and tangential

INTRODUCTION Neuronal migration is an essential process during corticogenesis by which postmitotic neurons displace from their birth place to reach target positions within Correspondence to: Melissa Barber ([email protected]) or Alessandra Pierani ([email protected]). Contract grant sponsor: NeRF (Neurop^ ole de recherche francilien). Contract grant sponsor: CNRS (Centre National de la Recherche Scientifique) Investigator. Contract grant sponsor: Ecole des Neurosciences de Paris Ilede-France (ENP). Contract grant sponsor: Agence Nationale de la Recherche; contract grant number: ANR-2011-BSV4-023-01. Contract grant sponsor: Fondation pour la recherche Medicale (FRM); contract grant number: Equipe FRM DEQ20130326521.

development of the embryonic cerebral cortex in a noncell-autonomous manner. While CRs have been extensively studied, it is only in the last decade that the molecular mechanisms governing their tangential migration have begun to be elucidated. To date, the mechanisms of SPs and CPTs tangential migration remain unknown. We therefore review the known signaling pathways, which regulate parameters of CRs migration including their motility, contact-redistribution and adhesion to the pial surface, and discuss this in the context of how CR migration may regulate their signaling activity in a spatial and temporal manner. VC 2015 Wiley Periodicals, Inc. Develop Neurobiol 00: 000–000, 2015

Keywords: tangential migration; glutamatergic neurons; Cajal-Retzius cells; subplate neurons; cortical plate transient neurons; cortical patterning

the developing cortical plate. This is a prerequisite for the correct laminar formation of the cerebral cortex and for the formation of functional neural circuits. In the developing cerebral cortex, neuronal migration can be broadly divided into two modes of migration: Contract grant sponsor: Ville de Paris; contract grant number: 2006 ASES 102. Contract grant sponsor: Association pour la Recherche sur le Cancer (ARC); contract grant number: SFI20111203674. Contract grant sponsor: Federation pour la Recherche sur le Cerveau (FRC). Conflict of Interest: Authors have no conflicts of interest. Ó 2015 Wiley Periodicals, Inc. Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/dneu.22363

1

2

Barber and Pierani

transient cells (CPTs) [Fig. 2(a)], which will be introduced below (De Carlos et al., 1996; Hevner et al., 2003; Takiguchi-Hayashi et al., 2004; Bielle et al., 2005; Yoshida et al., 2006; Teissier et al., 2010; Pedraza et al., 2014).

Transient Glutamatergic Neurons

Figure 1 Tangential and radial migration in the developing cerebral cortex. Cartoon shows the dorsal-lateral pallium from a rostral coronal section of an E11.5 developing mouse cerebral cortex, and illustrates the tangential migration (gray arrow) of neurons (gray cells) within the developing PP, which follow a trajectory parallel to the pia and orthogonal to the basal processes of radial glia (RG). Black arrow shows the radial migration of neurons generated in the neocortical germinal VZ, which migrate orthogonal to the pia and along RG basal processes (hatched cells). (PP: preplate; VZ: ventricular zone).

radial and tangential (Fig. 1). Radial migration is defined by the movement of neurons parallel to the basal processes of neuroepithelial and radial glial progenitors (RG), which comprise the primary germinal ventricular zone (VZ) of the pallium (Fig. 1, black arrow); and by a trajectory perpendicular to the pia membrane, which is the inner layer of the meninges that encompasses the surface of the developing forebrain. Tangential migration is defined by neurons migrating parallel to the pial surface and perpendicular to the radial glial palisade (Fig. 1, gray arrow). These two modes of migration have been classically associated with two major neuronal populations: (1) Glutamatergic pyramidal neurons, which are derived from pallial progenitors and migrate radially to form the overlying cortical plate (Rakic, 1978; Walsh and Cepko, 1988; Nadarajah et al., 2003; Noctor et al., 2004) and (2) GABAergic interneurons, which are generated from subpallial progenitors within the ganglionic eminences and migrate tangentially over longer distances to integrate into cortical layers (Anderson et al., 1997; Lavdas et al., 1999; Anderson et al., 2001; Nery et al., 2002; Tamamaki et al., 2003; Welagen and Anderson, 2011). Whereas it was previously believed that only GABAergic interneurons undergo tangential migration, the last decade has revealed that several major classes of transient glutamatergic neurons also migrate tangentially. These include glutamatergic CRs, subplate cells (SPs), and the novel population of cortical plate Developmental Neurobiology

Cajal-Retzius Cells (CRs). CRs are the first born neurons in the developing mouse cerebral cortex and are a pioneering neuronal population in the human fetal cortex (Konig et al., 1977; Raedler and Raedler, 1978; Marin-Padilla, 1983; Valverde et al., 1995; Meyer and Goffinet, 1998; Hevner et al., 2003; Rakic and Zecevic, 2003; Cabrera-Socorro et al., 2007). CRs are strategically positioned within the superficial preplate (PP) [Fig. 2(a)] and marginal zone (MZ) throughout corticogenesis, where they are best known for regulating the radial migration of pyramidal neurons and the formation of cortical layers through their secretion of the extracellular matrix protein Reelin (Falconer, 1951; D’Arcangelo et al., 1995; Ogawa et al., 1995; D’Arcangelo, 2006; Sekine et al., 2014). CRs are in close proximity to the basal processes of RG and Reelin is also thought to promote the molecular and morphological maturation of RG and to regulate neurogenesis (Soriano et al., 1997; Super et al., 2000; Hartfuss et al., 2003; Lakoma et al., 2011). In addition, CRs influence the differentiation of upper layer neurons (Kupferman et al., 2014), the invasion of the cortex by GABAergic interneurons (Hevner et al., 2004; Yabut et al., 2007; Caronia-Brown and Grove, 2011), cortical patterning (Griveau et al., 2010; Barber et al., 2015) and participate in the correct targeting of commissural and entorhinal projections in the hippocampus (del Rio et al., 1997; Super et al., 1998; Borrell et al., 1999). CRs are generated from E9.5 in the mouse, with a peak generation between E10 and E11 (Konig et al., 1977; Raedler and Raedler, 1978; Hevner et al., 2003; Takiguchi-Hayashi et al., 2004; Bielle et al., 2005; Gu et al., 2011). While CRs were thought to be derived from the neocortical VZ based on their expression of pallial markers (Tbr1, Tbr2, Emx1/2), and to migrate radially to form the early PP (del Rio et al., 1995; Marin-Padilla, 1998; Hevner et al., 2003), neurons expressing the CR cell-marker, Reelin, were observed adjacent to the retrobulbar ventricle. This first suggested that CRs may originate outside the neocortical VZ and may migrate tangentially to invade the MZ (Meyer et al., 1998; Meyer and Wahle, 1999). Subsequent genetic tracing studies, which allow progenitors and their derived postmitotic progeny to be permanently traced, showed

Tangential Migration of Glutamatergic Neurons

3

Figure 2 Transient glutamatergic neurons migrate tangentially from focal sources at the borders of the developing pallium. (a) Schema shows a transverse section through the dorsallateral part of an E12.5 mouse developing cerebral cortex at rostral levels along the rostral-caudal axis, and illustrates the tangential migration of CRs (green cells) in the upper PP, and of SPs from the RMTW (purple cell) and CPT neurons (red hatched cells) in the lower PP. Subpopulations of SPs generated in the pallial VZ also migrate radially (Ncx-SPs, black cells) to form the PP. (RG: Radial glia; bm: pial basement membrane). (b) Cartoons showing coronal sections through an E11.5-E12.5 mouse developing cerebral cortex at rostral (b, left) and caudal (b, right) levels along the rostral-caudal axis, illustrating sources of CR subtypes at the Septum (S, green), pallialsubpallial boundary (PSB, red) and cortical hem (CH, blue) as well as a source of a subpopulation of SPs at the RMTW (purple), and depicting their respective tangential migration routes between E10.5 and E12.5 (arrows, color-coded according to their source). Black arrows show the radial trajectories of a subpopulation of SPs generated in the neocortical germinal VZ, which migrate radially. CPTs are generated from the caudal PSB (cPSB, red hatched) from E12.5. (Cing, cingulate cortex; NCx, neocortex; Hipp, hippocampus; Pir, piriform cortex; CPe, choroid plexus; Eth, eminentia thalami).

the extraneocortical origins of CR subtypes (Takiguchi-Hayashi et al., 2004; Bielle et al., 2005; Yoshida et al., 2006; Zhao et al., 2006; Imayoshi et al., 2008; Tissir et al., 2009). While the precise migratory behavior and paths of cells can only be directly assessed by timelapse microscopy, genetic-tracing studies together with focal electroporation and/or injection of tracers strongly supported the notion that CRs originate in focal sources at the borders of the developing pallium and that they migrate tangentially to cover the cortical surface [Fig. 2(b)] (TakiguchiHayashi et al., 2004; Bielle et al., 2005; Yoshida et al., 2006; Zhao et al., 2006; Imayoshi et al., 2008; Tissir et al., 2009). The tangential migration of CRs was further confirmed in an experimental system in which fluorescent tracers were injected into the cortical hem (CH), and whole embryos subsequently cultured in toto (Garcia-Moreno et al., 2007). CR sources are specified by, or associated with, forebrain organizing centers and genetic tracing has shown these comprise: the cortical hem [blue in Fig. 2(b)]

(Takiguchi-Hayashi et al., 2004; Yoshida et al., 2006; Tissir et al., 2009; Gu et al., 2011), the pallial septum, located adjacent to the rostral organizing centre and likely corresponding to the previously believed retrobulbar source [green in Fig. 2(b)] (Bielle et al., 2005; Zimmer et al., 2010) and the ventral pallium at the pallial-subpallial boundary (PSB) or “anti-hem” [red in Fig. 2(b)] (Bielle et al., 2005). In addition, extrapallial CR sources have been identified based on genetic tracing and tracer-labeling studies, which include the choroid plexus (Cpe) [orange in Fig. 2(b)] (Imayoshi et al., 2008) and the Eminentia thalami (Eth) [light brown in Fig. 2(b)]. The Eth is a suggested CR source based on expression studies of Reelin, p73 and LIM-homeodomain (Lhx) transcription factors, and the analysis of Lhx2 mutants (Cabrera-Socorro et al., 2007; Tissir et al., 2009; Abellan et al., 2010a; Roy et al., 2014). A study followed the fate of cells derived from the septum area/S and ventral pallium/PSB, by labeling progenitors with fluorescent tracers exo utero at E10-E11, and whole Developmental Neurobiology

4

Barber and Pierani

embryos subsequently cultured for 24 h (Ceci et al., 2012). This showed that labelled cells, which expressed markers typical of CR cells, failed to migrate to the dorsal cortex, but gave rise to neurons, which populate the olfactory cortex. Based on these experiments, this study refuted the existence of S and PSB as sources of CR subtypes (Ceci et al., 2012). However, a recent live-imaging study of whole flattened cortices in which CR subtypes from the S, PSB, and CH were genetically labelled, has confirmed that CR subtypes invade the cortical surface from all three sources, with subtypes additionally showing differences in their onset of migration, direction of migration, and migration kinetics (Barber et al., 2015). The whole-embryo culture system closely mimics and preserves the in vivo anatomical and molecular environments of migrating cells, however, discrepancies with previous genetic tracing studies which in addition used DiI tracing on slices of genetically label embryos (Bielle et al., 2005; Griveau et al., 2010; Zimmer et al., 2010) and the recent imaging study (Barber et al., 2015) could arise because of in vitro culture conditions and/or the technical difficulties in focally targeting tracers to progenitor subdomains. Further, tracer injection does not enable one to discern the progeny of labeled progenitors from cells, which may migrate through the injection site. Thus, future studies using whole-embryo cultures of transgenic mice in which CRs are genetically traced combined with fluorescent tracer injections exo utero, are required to resolve these discrepancies. Nevertheless, the large body of data and current consensus in the field is that the PSB and S are bonafide sources of CR subtypes, and that molecularly distinct CR subtypes originate from multiple extraneocortical sources and differentially populate cortical territories (Takiguchi-Hayashi et al., 2004; Bielle et al., 2005; Borrell and Marin, 2006; Yoshida et al., 2006; Zhao et al., 2006; Hanashima et al., 2007; Tissir et al., 2009; Griveau et al., 2010; Zimmer et al., 2010; Gu et al., 2011; Chiara et al., 2012; Villar-Cervino et al., 2013; Trousse et al., 2015). Lineage-tracing experiments of progenitors which express the developing brain homeobox 1 (Dbx1) transcription factor in the pallial septum and PSB, have shown these give rise to molecularly distinct CR subtypes (Fig. 3; Bielle et al., 2005; Griveau et al., 2010). Dbx1-CR subtypes initiate their migration at E10 in the mouse, and follow a subpial route to cover the cortical surface by E12, as inferred by genetic tracing. Molecularly distinct subtypes have further been shown to distribute in a complementary manner at the cortical surface, with pallial septum Developmental Neurobiology

derived-Cajal-Retzius subtype (S-CRs) populating the rostral-medial pallium (green dots in Fig. 3), cortical hem-derived Cajal-Retzius subtype (CHCRs) the caudal-medial pallium (blue dots in Fig. 3) and ventral pallium-derived Cajal-Retzius subtype (PSB-CRs) the lateral pallium (red dots in Fig. 3; Bielle et al., 2005; Yoshida et al., 2006; Griveau et al., 2010). Expression studies of CR markers have also suggested that CRs derived from the ventral caudal medial telencephalic wall (CMTW) and Cpe [red, brown, orange dots in Fig. 3(b), respectively] populate the olfactory/piriform cortex (pir) (Meyer and Wahle, 1999; Meyer et al., 2002; Miquelajauregui et al., 2010; Dixit et al., 2014), and were confirmed to migrate to the pir together with CRs derived from the PSB in tracing studies (Bielle et al., 2005; Imayoshi et al., 2008), although their precise distributions have not been shown to date. While the territories Eth-CRs populate are not known, gene expression studies (Cabrera-Socorro et al., 2007; Tissir et al., 2009; Abellan et al., 2010a) combined with the observation that ablating CRs from the S or CH does not deplete CRs in the ventral telencephalon (Yoshida et al., 2006; Griveau et al., 2010), suggests Eth-CRs may migrate to cover ventral territories. The role of molecularly distinct CR subtypes in cortical development has started to be elucidated, and suggests that the composition of CRs at the cortical surface influences the tangential patterning of the cortical neuroepithelium (Griveau et al., 2010). CRs migrate at a time when the cortical neuroepithelium is regionalized (E10.5-E12.5; Cohen-Tannoudji et al., 1994; Shimamura and Rubenstein, 1997; Miyashita-Lin et al., 1999) and S-CR and PSB-CR subtypes have been shown to be differentially enriched in morphogens (Griveau et al., 2010). Genetic ablation of S-CRs or their progenitors resulted in a depletion of CRs in the rostral-medial cortex, and in the repopulation of the ablated area by CH- and PSB-CR subtypes one day later. This correlated with noncell-autonomous changes in gradients of transcription factors which regionalize the embryonic neuroepithelium, and in altered neurogenesis in affected territories (Griveau et al., 2010). Strikingly, a reduction in phospho-histone-3 (PH3) and bromodeoxy-uridine (BrdU) proliferative markers were observed within the rostral-medial VZ, which correlated with the depletion of S-CRs in these regions. In addition, an increase in proliferating PH31BrdU1 cells was observed in the rostral-dorsal germinal VZ, which correlated with the compensatory increased accumulation of PSB-CRs in these territories. Analysis at postnatal stages further showed that these early patterning defects resulted in the expansion of the


5

Figure 3 Complementary distribution of Cajal-Retzius subtypes in cortical regions. (a) Schema of the dorsal view of an E11.5 mouse developing cerebral cortex showing three pallial sources of CRs (left hemisphere) at the pallial septum (green, S), PSB (red), and CH (blue) and the tangential migration routes these follow to invade the dorsal cortex (arrows colour coded according to the source) from E10.5 to E12.5. Regional distribution of molecularly distinct S-CRs (green dots), PSB-CRs (red dots) and CH-CRs (blue dots) in rostral-medial, lateral and caudal-medial territories at E11.5-E12.5 (right hemisphere). (b) Cartoons of coronal sections taken at three levels (L1-L3) along the rostral-caudal axis of an E11.5 mouse cortex, showing the complementary regional distribution of CR subtypes in the pallium (S-CRs, green dots; PSB-CRs, red dots; CHCRs, blue dots). The specific distributions of CR subtypes derived from the choroid plexus (CPeCRs, orange dots), the ventral caudal telencephalic wall (vCMTW-CRs, brown dots), and the eminentia thalami (Eth-CRs, gray dots) remain unknown.

primary motor cortex. Thus, CR subtypes appear to act as “mobile patterning units” and signal to pallial progenitors to influence the spatial patterning and regionalization of the cortex and the formation of postnatal cortical areas (Griveau et al., 2010). Consistent with this, a recent study has shown that by genetically modulating the migration velocity of CR subtypes, this altered CRs specific distributions and compositions at the cortical surface which, in turn, resulted in changes in the size of secondary and association areas of the somatosensory, auditory and visual cortex at postnatal stages and in a congruent rewiring of thalamocortical afferents in primary somatosensory areas (Barber et al., 2015). These

studies raise the intriguing possibility that changes in the total number of CRs influence primary cortical area formation (Griveau et al., 2010), with changes in the specific composition of CR subtypes influencing the size of higher-order cortical areas (Barber et al., 2015). Indeed, during postnatal stages, CRs integrate into and shape cortical circuitry (Zhou and Hablitz, 1996; Zhou and Hablitz, 1996; Aguilo et al., 1999; Radnikow et al., 2002; Albrieux et al., 2004; Quattrocolo and Maccaferri, 2014). The persistence and fate of CRs at postnatal stages and in the adult cerebral cortex, however, remains unresolved. Early studies suggested that the reduced density of CRs may be a result of their dilution in an expanding adult cerebral Developmental Neurobiology

6

Barber and Pierani

cortex (Marin-Padilla and Marin-Padilla, 1982; Marin-Padilla, 1990), or that these may transform into GABAergic neurons (Parnavelas and Edmunds, 1983). This is consistent with the observed persistence of, although sparse, in the sparse CRs in the mouse hippocampal cortex and neocortex (MartinezGarcia et al., 1994; Duveau et al., 2011; MartinezGalan et al., 2014). Cells with the characteristic morphologies of CRs which express calcium binding proteins and reelin, are also reported in the adult human neocortex, entorhinal and hippocampal cortex (Belichenko et al., 1995; Martin et al., 1999; Meyer and Wahle, 1999; Abraham and Meyer, 2003; Riedel et al., 2003; Baloyannis, 2005; Camacho et al., 2014). More recently, there is a body of evidence in mice which suggests that CRs disappear during the first two postnatal weeks in part by apoptosis (Meyer et al., 1998; Abraham and Meyer, 2003; Chowdhury et al., 2010; Anstotz et al., 2014). CR cell degeneration has been visualized by labeling of CRs with horseradish peroxidase or by glutamate and Calretinin1 immunoreactivity, combined with electron microscopy (Derer and Derer, 1990; del Rio et al., 1995). This is consistent with observations of a 97% disappearance of Reelin1Gad672 immunoreactive cells in the postnatal mouse cortical layer I, corroborated by the morphological degeneration of CRs axons and dendrites (Ma et al., 2014). A proportion of CRs have also been shown to express activatedcaspase 3 consistent with these undergoing apoptosis (Chowdhury et al., 2010; Anstotz et al., 2014). Timelapse-imaging analysis of the cortex in situ in live postnatal embryos has directly shown that CR cells undergo degeneration during the second postnatal week with postimaging analysis showing that morphological changes were associated with the expression of activated caspase-3 in CRs (Chowdhury et al., 2010). This latter study directly confirmed that, at least some, CRs undergo apoptosis in the mouse. However, imaging was restricted to small cortical areas without quantifications and conflict with the reported persistence of CRs in the mouse cortex. The apparent discrepancies could perhaps be explained by subtype-specific differences in CR cell survival. Indeed, analysis of CR cell survival in organotypic cultures, has shown that Calretinin1 CR cells from the neocortex and hippocampus exhibited differences in their persistence in vitro (del Rio et al., 1996), raising the possibility that CR subtypespecific survival subtype could occur in vivo. This is consistent with immunolabelling (del Rio et al., 1995) and genetic tracing studies (Bielle et al., 2005;Yoshida et al., 2006;Tissir et al., 2009) which suggest that hem-derived CRs, which also populate Developmental Neurobiology

the hippocampal cortex (Takiguchi-Hayashi et al., 2004; Gu et al., 2011), persist longer than Dbx1derived CRs, the latter which disappear from the cerebral cortex in vivo postnatally. Whether speciesspecific differences in CR cell survival also occur remains to be investigated. Thus, the proportion and persistence of CRs in the postnatal and adult cerebral cortex remains an unresolved issue. CRs however serve crucial functions during embryonic and early postnatal development to (1) influence the tangential patterning and regionalization of the cortical neuroepithelium required for the formation of postnatal cortical areas, (2) locally regulate the radial migration of pyramidal neurons thereby orchestrating the correct laminar formation of the neocortex, and (3) shape cortical circuits. Subplate Neurons. SPs are early born neurons with

their peak generation at E11-E12 and a small percentage generated at E10, and which occupy a deeper position to CRs in the forming PP [Fig. 4(a) purple cells] (Luskin and Shatz, 1985; Chun and Shatz, 1989; Bayer and Altman, 1990; Kostovic and Rakic, 1990; Wood et al., 1992; Allendoerfer and Shatz, 1994; Price et al., 1997; Hoerder-Suabedissen and Molnar, 2013; Pedraza et al., 2014). As neurogenesis proceeds, the PP splits and SPs occupy a deep position below the cortical plate [SP in Fig. 5(a)] (Raedler and Raedler, 1978; Marin-Padilla, 1983; Luskin and Shatz, 1985). SPs have a crucial role in guiding thalamo cortical projections (TCA) to target cortical areas during development (Shatz and Luskin, 1986; Friauf et al., 1990; De Carlos and O’Leary, 1992; Ghosh and Shatz, 1993; Kanold et al., 2003; Shimogori and Grove, 2005) which is crucial for the activity-dependent refinement of primary cortical areas during postnatal stages and for the establishment of functional cortical columns (O’Leary, 1989; Gitton et al., 1999; Erzurumlu and Kind, 2001; Kanold et al., 2003; Lopez-Bendito and Molnar, 2003; Mallamaci and Stoykova, 2006; HoerderSuabedissen and Molnar, 2015). The innervation of TCA axons from the lateral geniculate nucleus to the primary visual cortex was also shown to drive the distinction between higher-order (secondary and association) and primary visual areas in the postnatal brain (Chou et al., 2013); however, the specific role of SPs in this process is unknown. In addition SPs guide corticofugal projections (McConnell et al., 1989, 1994), shape intracortical circuitry (Friauf and Shatz, 1991; Higashi et al., 2002; Kanold et al., 2003; Higashi et al., 2005; Pinon et al., 2009; Zhao et al., 2009; Meng et al., 2014), and promote the maturation of GABAergic inhibitory circuitry (Kanold et al., 2003). The increased prominence of the subplate in primates


7

Figure 4 Tangential migration of SPs and their distribution in cortical territories. (a) Cartoon shows the dorsal-lateral cortex of a rostral coronal section from an E11.5 mouse embryo, and illustrates the tangential migration of a subpopulation of SPs derived from the rostral medial telencephalic wall (RMTW-SPs, purple cells) at E10.5-E11.5, which follow a parallel trajectory to the pia and migrate in the lower PP below CRs (gray cells). Subpopulations of SPs (NCx-SPs, black cells) generated from RGs (elongated unipolar gray cells) in the neocortical VZ migrate orthogonal to the pia and parallel to basal processes. (b) Schema of the dorsal view of the embryonic mouse cerebral cortex. Left hemisphere shows the origin of SPs from the RMTW (purple) at E10.5-E11.5, and their tangential migration trajectories to invade the PP at E11.5-12.5 (purple arrows). Right hemisphere shows the predicted rostral-caudal migration of RMTW-SPs (purple dots) as they invade the cortex from E11.5. Left hemisphere of second schema shows the unknown distribution of RMTW-SPs (purple dots) and of calretinin1 (gray dots) and calretinin– (gray dots with black contours) subplate subtypes, which migrate radially from their origins in the neocortical VZ at E13. At P0.5 (right hemisphere) a rostral-caudal gradient of RMTW-SPs has been reported with hypothetical distributions shown accordingly. (CR: CajalRetzius cells; RMTW-SP: SP derived from the RMTW; Calr: Calretinin). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

and humans (Kostovic and Rakic, 1990; Smart et al., 2002; Wang et al., 2011a) has led to the theory that the emergence of the subplate may have contributed to the increased complexity of cortical circuitry and function during evolution (Luhmann et al., 2009; Montiel et al., 2011; Wang et al., 2011a; Judas et al., 2013; Hoerder-Suabedissen and Molnar, 2015). SPs were previously believed to originate in the pallial VZ and to migrate radially to form the PP.

This was based on birth-dating studies using tritiated thymidine and BrdU, which showed radially oriented labeled cells within the lower PP, and based on SPs expression of pallial markers and polymorphous morphologies, the latter which distinguished them from CRs (Valverde et al., 1995; Meyer et al., 1998; Meyer et al., 2000; Hevner et al., 2001; Jimenez et al., 2003). However, a study using in utero retroviral and dye tracer injections, has shown that while Developmental Neurobiology

8

Barber and Pierani

Figure 5 Tangential migration and invasion of cortical territories by CPTs. (a) Schemas of a rostral (left) and a caudal (right) coronal section from an E12.5 mouse developing cerebral cortex showing the site of generation of CPTs within the caudal PSB (cPSB, red hatched) and the tangential migratory trajectories these follow along a caudal-lateral to rostral-medial route (red hatched arrows). Boxed regions correspond to the dorsal-lateral pallium and are enlarged in adjacent panels showing the positions of migratory streams of CPTs (red hatched cells) at the boundary of the lower intermediate zone/subventricular zone (LIZ/SVZ) and subplate (SP). CPTs invade the caudal cortical plate (CP) before these arrive in the rostral cortical plate. (b,c) Cartoons of the lateral surface of an E12.5 (left) and E14.5 (right) mouse cerebral cortex showing the migration of CPTs (red hatched arrows) along a progressive caudal-lateral to rostral-medial trajectory (b) and their corresponding progressive invasion and distribution in the developing cortical plate over time (red dots). (MZ: marginal zone; bm: basement membrane; CR: Cajal-Retzius subtypes; SP: subplate neuron; IP: intermediate progenitor; I: interneuron). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

SPs indeed derive from the pallial VZ [black arrows and cells in Figs. 2 and 4(a,b)], a proportion also originate from an extra-neocortical source within the rostral medial telencephalic wall (RMTW) [purple in Fig. 2(b) and purple cells in Fig. 4(a,b)]. This latter subpopulation is generated over a short period (E10E11) and disperses along a caudal and dorsal gradient [purple arrow and cells in Figs. 2(b) and 4(b)], to become homogeneously distributed throughout the rostral-caudal extent of the PP and subsequently within the subplate as the cortical plate forms (Pedraza et al., 2014). While SPs are homogenously distributed at embryonic stages, their graded rostralcaudal distribution is reported at birth (Pedraza et al., 2014), perhaps reflecting differences in SPs survival [Fig. 4(b)]. In addition, two distinct Calretinin positive and negative SP subtypes appear to be generated in the neocortical VZ at E10 and E11, respectively, and disperse radially to form the PP (gray and black Developmental Neurobiology

dots in Fig. 4). Thus, this study suggested that, similar to CRs, SPs may comprise molecularly heterogeneous subtypes, which arise from distinct sources (Pedraza et al., 2014). Indeed, gene expression studies show molecular and regional heterogeneity of SPs (Hoerder-Suabedissen et al., 2009; HoerderSuabedissen and Molnar, 2012, 2013), however, their lineages and origins remain unknown. Future studies should address whether regional distributions of SP subtypes play a role in the area-specific targeting of TCA and intracortical projections, or if subtypes exert distinct functions. There is still some controversy regarding the persistence of SPs in the adult cerebral cortex. While early reports suggested they undergo cell-death postnatally (Kostovic and Rakic, 1990; Allendoerfer and Shatz, 1994; Price et al., 1997; Kanold et al., 2003), other studies showed these persisted and comprised interstitial neurons in the white matter of adult primates (Kostovic and


Rakic, 1990) or layer VIb in the adult rodent cortex (Cobas et al., 1991; Woo et al., 1991; Valverde et al., 1995; Reep, 2000). These discrepancies are in part due to species-specific (Kostovic and Rakic, 1990; Allendoerfer and Shatz, 1994; Valverde et al., 1995; Wang et al., 2011a) and regional-specific differences (Kostovic and Rakic, 1990) in their persistence, confounded by the lack of specific early subplate markers (Hoerder-Suabedissen et al., 2009). However, retroviral and dye injection tracings, and gene expression studies, suggest that early born SPs persist at least into the first postnatal week, and raise the possibility that their survival may depend on the specific subtype (Hoerder-Suabedissen et al., 2013; Pedraza et al., 2014). SPs are enriched in genes associated with autism and schizophrenia (Eastwood and Harrison, 2006; Hoerder-Suabedissen et al., 2013), suggesting that aberrant subplate development may alter cortical circuitry implicated in these cortical pathologies. Thus, the correct migration and positioning of SPs, as that of CRs, might influence the formation of functional cortical areas and circuitry. While the mechanisms of SPs migration have not been investigated, they are thought to adopt both tangential and radial modes of migration, depending on their respective origins within the RMTW or neocortical VZ. Timelapse studies have shown that early-born projection neurons migrate from the neocortical VZ by somal translocation (Miyata et al., 2001; Tamamaki et al., 2001; Nadarajah et al., 2003), with later-born neurons undergoing locomotion (O’Rourke et al., 1992; Hatanaka et al., 2004; Noctor et al., 2004), which includes phases of multipolar radial migration (Tabata and Nakajima, 2003; Noctor et al., 2004; Hatanaka et al., 2004) and terminal phases of somal translocation (Miyata et al., 2001; Nadarajah et al., 2001; Tamamaki et al., 2001). Understanding how SPs radial migration is coordinated with the tangential migration of SPs derived from the RMTW and how this correlates with the splitting of the PP remain to be investigated. CPT Cells. CPTs are a novel population of transient

glutamatergic neurons which our group identified using genetic tracing from Dbx1 progenitors, DiI injection and transplants. CPTs were shown to be generated from Dbx1-expressing pallial progenitors in the caudal PSB [red hatched region in Figs. 2(b) and 5(a)] (Teissier et al., 2010) from E11.5 to E14.5, with a peak generation at E12.5. These were shown to initiate their tangential migration from the caudal PSB at E12.5 and to follow trajectories along the subplate and at the boundary of the lower intermediate zone and the germinal subventricular zone (LIZ/

9

SVZ), from where these invade the cortical plate in a caudo-lateral to rostral-medial gradient, and to reach rostrodorsal territories by E14.5 (Fig. 5). At P0, CPTs comprise less than 5% of the total glutamatergic neuronal population, express layer-specific markers, and are homogeneously distributed along the rostral-caudal extent of the cortical plate, with their position preferentially in deep cortical layers largely corresponding with their birth-date [Fig. 5(c)]. CPTs have been shown to undergo apoptosis during the first postnatal week (P0-P8). Genetic ablation studies using a Cre-Lox strategy to ablate Dbx11 progenitors in the caudal PSB at E12.5 (Teissier et al., 2012) have shown that CPTs play a crucial role in noncell-autonomously regulating neurogenesis. Ablation of CPTs resulted in the noncell-autonomous lengthening of the cell-cycle of cortical progenitors and an increase in their neurogenic divisions (Teissier et al., 2012). This precocious neurogenesis resulted in the depletion of progenitor pools, which normally give rise to upper layer neurons and in a significant thinning of the cortical plate throughout the cortex. Strikingly, the observed defects in neurogenesis correlated with CPTs migration trajectories. CPTs thus appear to regulate the timing of cell cycle exit, the onset of neurogenic divisions, and the radial growth of the cortex. Further research on CPTs has so far been hindered by the lack of specific molecular markers except for genetic tracing, thus limiting studies on this population. Nevertheless, although the mechanisms which underlie the migration of CPTs are unknown, their tangential migratory routes parallel those of cortical interneurons within the subplate and LIZ/SVZ (Teissier et al., 2010), raising the possibility that CPTs migration may be governed by similar guidance molecules to cortical interneurons (Stumm et al., 2003; Flames et al., 2004; Hevner et al., 2004; Pla et al., 2006; Tanaka et al., 2006; Lopez-Bendito et al., 2008; Lysko et al., 2011; Tanaka and Nakajima, 2012).

Shared Characteristics of Distinct Classes of Transient Glutamatergic Neurons All three transient glutamatergic neurons appear to share common characteristics. First, these are generated from focal progenitor domains located at the borders of the pallium. Second, these migrate tangentially to invade the neocortex. Third, these are mostly transient populations of neurons, which undergo programmed cell death during postnatal stages, and thus have a confined role during development. Lastly, all three transient populations of neurons have crucial Developmental Neurobiology

10

Barber and Pierani

roles in orchestrating the tangential (CRs, SPs) and radial (CRs, CPTs, SPs) patterning of the cerebral cortex in a noncell-autonomous manner. Understanding the mechanisms by which they migrate to become strategically positioned both temporally and spatially in cortical territories is therefore crucial to understand their signaling and patterning role during development; and has implications in understanding how migration disorders of transient neurons may be implicated in neurodevelopmental and neuropsychiatric disorders. The molecular mechanisms by which CPTs and SPs migrate are not known, however CPTs migrate along similar trajectories to cortical interneurons and SPs express several genes shown to be involved in CR migration. This suggests CPTs, SPs, CRs, and possibly cortical interneurons might share some of the pathways regulating their movement. We therefore review the mechanisms of CRs migration and discuss this in light of how this may affect their signaling activity in a spatial and temporal manner to impact the development of the cerebral cortex. CR migration comprises several striking features. First, CRs are localized at the surface of the forebrain throughout corticogenesis, which is crucial for their strategic signaling activity and their regulation of cortical lamination. Second, these first-born neurons migrate along a unique substrate, the pial basement membrane, which encompasses the cerebral cortex. Thirdly, molecularly distinct subtypes invade complementary regions in the MZ and distribute in a highly specific manner, which is crucial for their role in the tangential patterning of the cortex. We therefore review the known molecular mechanisms, which influence (1) the integrity of CRs migratory substrate, (2) the confinement of CRs to their subpial positions, and (3) their tangential invasion in cortical territories.

CRs SUBPIAL POSITIONING Integrity of CRs Migratory Substrate: The Pia Membrane The pia is the inner layer of the meninges, which comprises a rich network of blood vessels, a layer of pial cells and loosely interspersed fibroblasts (Ramsey, 1965; Lopes and Mair, 1974; Krisch et al., 1983, 1984; Alcolado et al., 1988; Etchevers et al., 2001; Le Douarin et al., 2007; Zarbalis et al., 2007; Vasudevan et al., 2008). These cells secrete extracellular matrix proteins which tether to the pial and vascular membranes and form a continuous basement membrane at the surface of the brain. These include: fibronectin, collagens (I, III, IV, VI), nidogen, memDevelopmental Neurobiology

bers of the laminin family and heparin sulphate proteoglycans such as perlecan and agrin (Sievers et al., 1994; Arikawa-Hirasawa et al., 1999; Costell et al., 1999; Libby et al., 2000; Moore et al., 2002; Luo et al., 2011; Luo et al., 2011; Li et al., 2012), and thus comprise a rich haptotactic (tethered cues) migratory substrate. In addition to extracellularmatrix proteins, the meninges are enriched in various secreted signaling molecules that are crucial for cortical development. These include: retinoic acid, the secreted chemokine C-X-C subfamily member, Cxcl12, the bone morphogenetic protein members, BMP7/BMP4, transforming growth factor molecules, TGF-ß (Yoshida and Gage, 1991; Smith et al., 2001; Siegenthaler et al., 2009; Segklia et al., 2012; Choe et al., 2014; Kusakawa et al., 2015) and brain-derived and neurotrophic growth factors, BDNF and NT4 (Maisonpierre et al., 1990; Brunstrom et al., 1997; Fukumitsu et al., 1998; Ringstedt et al., 1998; Niclou et al., 2003; Shearer et al., 2003; Alcantara et al., 2006; Segklia et al., 2012). In addition, semaphorin proteins are secreted from meningeal cultures in vitro (Marin et al., 2001; Shearer et al., 2003; Tamamaki et al., 2003; Niclou et al., 2003), which are known for their role in guiding growing axons and migrating interneurons in the forebrain (Bagri and TessierLavigne, 2002; Kruger et al., 2005). CRs apposition to the pia membrane strategically positions them close to the basal processes of RGs, which anchor their endfeet to its surface (Fig. 6), and which comprise the main progenitors of pyramidal neurons in the mouse cerebral cortex (Florio and Huttner, 2014). In addition, CRs migrate adjacent to SPs and cortical interneurons, which are located in the lower PP and MZ. CRs are also ideally positioned to interact with the leading processes of radially migrating pyramidal neurons as these approach the MZ during their terminal phases of migration. Thus, the superficial position of CRs is crucial for their strategic signaling activities. Early studies in which the meninges were physically, chemically, or genetically perturbed first suggested that the meninges may be important in the subpial positioning and survival of CRs (Super et al., 1997; Hartmann et al., 1999; Super et al., 2000; Graus-Porta et al., 2001; Halfter et al., 2002; WinesSamuelson et al., 2005; Zarbalis et al., 2007; Zarbalis et al., 2012; Radner et al., 2013). Experiments in which the neurotoxic drugs 6-hydroxydopamine or domoic acid were topically applied to the cortical surface showed these resulted in the degeneration of the meninges and in a loss of CRs, suggesting that the meninges may provide important trophic support (Super et al., 1997, 2000). Subsequent genetic invalidation studies which targeted extracellular matrix

Figure 6 Subpial positioning of Cajal-Retzius subtypes. (a) Cartoons showing the superficial positioning of S-CR (green), CH-CR (blue), and PSB-CR (red) within the PP in the wildtype cerebral cortex, located below the pial basement membrane (bm) and in close association with radial glia (RG) progenitors endfeet. (b) Ablation of extracellular matrix protein constituents (Nidogen12/2 or Laminin ß22/2/Ç32/2) or (c) of specific matrix-protein receptors within RGs endfeet (DAG12/2, GPR562/2) results in the retraction of RG endfeet from the pia surface, basement membrane degradation, and in the overmigration (c) or deep ectopic positioning (b, d) of CRs (dark gray cells). (d) RGs deficient in integrinß1 receptors results in deep ectopic positions of CRs especially in the lateral and caudal cortex suggesting these may correspond to PSB-CRs (red cells) and CH-CRs (blue cells). (e) Mouse mutants deficient in Cxcl12/Cxcr4/Cxcr7 signalling show this differentially regulates CH-CR (blue cells) and PSB-CR (red cells) subtypes positions, due to their differential expression of Cxcr41/Cxcr71 and Cxcr71 receptors, respectively. The role of Cxcl12 signalling in S-CRs superficial distributions remain unknown (not shown). (f) Schema illustrating the pia membrane which comprises vascular endothelial cells (vEC) and pial cells (PC) (not shown) which secrete matrix-proteins including collagenIII (brown undulations), laminin (gray undulations) and fibronectin (black undulations) which form the basemement membrane (bm). Radial glia progenitors (RG) anchor their endfeet to specific matrix-proteins through cognate receptors (integrinß1, GPR56, DAG) and interact with CRs (dark gray cell) to confine their positions within the superficial MZ by an unknown mechanism (arrows and red points suggesting RGs contact with CRs). CXCL12 (black hexagons) is secreted by the overlying meninges, which bind and signal through their cognate CXCR4 (black) and CXCR7 (green) receptors expressed by CRs maintaining their subpial positions. CRs secrete reelin (yellow dots), which promote RGs morphological differentiation, biochemical maturation, and anchorage to the basement membrane.

12

Barber and Pierani

components of the pial basement membrane, including the laminin ß2 and Ç3 chains, or the nidogen-1 binding sites in the laminin Ç1 chain, showed this resulted in the disintegration of regions of the pia membrane, the retraction of RG endfeet from the pia, a disordered radial glial scaffolding and in the ectopic positioning of CRs deep within the cortical parenchyma in regions where the pia was absent [Fig. 6(b)] (Halfter et al., 2002; Radner et al., 2013). These studies suggested that the integrity of the pia basement membrane is necessary for the confinement of CRs in the MZ. RGs endfeet adhesion to the pia membrane have in turn been shown to influence the matrix-protein composition of the pia basement membrane through an unknown non-cell-autonomous mechanism (Dulabon et al., 2000; Graus-Porta et al., 2001; Moore et al., 2002; Li et al., 2008b; Luo et al., 2011; Myshrall et al., 2012; Singer et al., 2013). Receptors that bind to specific matrix-protein ligands are localized to RG endfeet, and include integrin receptors and a brain form of the dystrophin glycoprotein (DG) which both binds to laminin and GPR56, a member of the adhesion G-protein coupled receptor family, which binds to collagen III (COL3AI). Targeted genetic invalidation of these receptors in RGs have shown this results in a disintegration of the pial basement membrane, which correlates with the ectopic localization of CRs in the meningeal space (DAG1 and GPR56) [Fig. 6(c)] or deep within the cortical plate (integrin ß1) [Fig. 6(d)]. Intriguingly, ablation of integrin ß1 receptors in RGs also results in a noncell-autonomous degradation of extracellular matrix proteins including laminin, collagen IV, nidogen and entactin (Graus-Porta et al., 2001). This latter study suggests that correct targeting of RG endfeet to the pia affects the integrity and the matrix-protein composition of CRs physical migratory substrate, and possibly in CRs positioning. Genetic invalidation of matrix-proteins in the pial basement membrane, or of their binding receptors in RG endfeet, show this results in region-specific defects in the pia membrane and in CRs positioning in the cortex. While invalidation of laminins ß2Ç3 results in pial and CRs defects specifically in the medial cortex and ventral pallium (Radner et al., 2013), perturbing integrin ß1 or GPR56 in RGs results in severe defects in the rostral-medial/frontal regions of the cortex (Singer et al., 2013). Together, these studies suggest region-specific defects in CR positioning which correlates with regional differences in pia basement-membrane matrix-protein composition and which is consistent with the observation of gradients of different laminin isoforms within the meninges (Li et al., 2012; Radner et al., 2013). CRs Developmental Neurobiology

have in turn been suggested to regulate the radial glial scaffolding through their secretion of Reelin, by promoting the branching, differentiation and anchoring of RG endfeet to the pia membrane (Super et al., 2000; Forster et al., 2002; Hartfuss et al., 2003; Luque et al., 2003; Chai et al., 2014). Thus, a regulatory loop between CRs, RG, and the pia membrane may exist [Fig. 6(f)].

Cxcl12 Regulates CRs Subpial Positions While the above studies suggested that an intact pia membrane may be required for CRs subpial positioning, subsequent in vitro studies reported that the pia was also an essential migratory substrate for CRs. This was based on the observation that physically removing the meninges from a region of the cerebral cortex in slice cultures inhibited the migration of CRs from the hem (Borrell and Marin, 2006). Coculture experiments of meningeal and hem explants in vitro further suggested that the meninges secreted a diffusible chemoattractant, which CH-CRs responded to (Borrell and Marin, 2006). The chemokine C-x-c subfamily member Cxcl12/ Sdf1 is secreted by meningeal cells providing a homogenous source of Cxcl12 at the surface of the brain, and has been shown to be a major signaling pathway regulating the subpial position of CH-CRs and PSB-CRs in the developing cerebral cortex [Figs. 6(e) and 7] (Borrell and Marin, 2006; Paredes et al., 2006; Tiveron et al., 2010; Zarbalis et al., 2012; Trousse et al., 2015). This secreted chemokine was originally identified as a chemoattractant in the immune system and to signal through its cognate Gprotein linked 7-pass transmembrane receptor Cxcr4 (Tashiro et al., 1993; Shirozu et al., 1995; Bleul et al., 1996; Nagasawa et al., 1996; Ganju et al., 1998). Cxcl12 regulates the migration of diverse cell types in the nervous system including cortical interneurons (Ma et al., 1998; Klein et al., 2001; Bagri et al., 2002; Zhu et al., 2002; Stumm et al., 2003; Tiveron et al., 2006; Schwarting et al., 2006; LopezBendito et al., 2008; Yang et al., 2013). In addition, a second Cxcr7 receptor which also promotes cell migration (Dambly-Chaudiere et al., 2007; Valentin et al., 2007; Boldajipour et al., 2008; Cubedo et al., 2009) was subsequently identified (Burns et al., 2006; Sierro et al., 2007; Luker et al., 2010). The conserved DRYLAIV motif, which is crucial for G protein coupling and Ca21 signaling, is altered in the Cxcr7 receptor and it has been suggested to act as an atypical chemokine receptor (Boldajipour et al., 2008; Luker et al., 2010; Naumann et al., 2010; Sanchez-Alcaniz et al., 2011; Hoffmann et al., 2012;


13

Figure 7 Molecular mechanisms that regulate CRs tangential migration. Cartoon showing coronal sections through an E11.5 mouse developing cortex at rostral and caudal levels along its rostral-caudal axis showing the graded expression of secreted class III semaphorins (Sem3E; purple) in the underlying cortical parenchyma which is expressed in a decreasing dorsal-medial to lateral gradient at middle (not shown) and caudal levels of the developing cortex. Sema3E negatively regulates the motility and speed of migration of PlexinD1-expressing CH-CRs (blue cells) from the cortical hem (blue) by activating intracellular ERK1/2 signalling and Actin/Cofilin and modulating CH-CRs response to the chemokine CXCL12, which is homogenously expressed in the meninges (pink). VAMP3 negatively modulates S-CR and CH-CRs migration speed cell-autonomously. CRs migrate by Eph/ephrin-mediated contact repulsion to disperse in the cortex with Sema3E controlling the extent of invasion of CH-CRs in the caudal cortex. PSB-CRs (red), S-CRs (green), and CH-CRs (blue) differentially express CXCL12 receptors (CXCR4, CXCR7) and transcriptional regulators of migration (Ebf2, Ebf3, Lhx5).

Abe et al., 2014). Cxcr7 is thought to act as a scavenger receptor and to mop up Cxcl12 in the microenvironment, thereby modulating Cxcr4-mediated responsiveness to Cxcl12 (Sanchez-Alcaniz et al., 2011; Abe et al., 2014), and/or shaping Cxcl12 gradients to establish directional migration in a cellautonomous (Dona et al., 2013; Venkiteswaran et al., 2013), or noncell-autonomous manner (Boldajipour et al., 2008; Memi et al., 2013). Cxcr4 and Cxcr7 receptors show a dynamic and CR subtype-specific pattern of expression (Borrell and Marin, 2006; Paredes et al., 2006; Berger et al., 2007b; Tiveron et al., 2010; Trousse et al., 2015). Cxcr7 is expressed in early born CRs which are positioned throughout the MZ, with later migrating CHCRs expressing Cxcr4 from E11 and throughout corticogenesis, whereas Cxcr7 is largely downregulated by E14.5 (Wang et al., 2011b; Trousse et al., 2015). CRs also express the ligand Cxcl12 during mid and late stages of corticogenesis at a time when Cxcr4 is expressed by CH-CRs (Paredes et al., 2006; SanchezAlcaniz et al., 2011; Zarbalis et al., 2012). These dynamic expression patterns suggest temporal and subtype-specific differences in Cxcl12 signaling as

CRs migrate to become positioned in the cerebral cortex. In vitro experiments in which CH explants were confronted with a secreted source of Cxcl12, showed that addition of this chemokine promoted CR chemoattraction, but was abrogated upon chemical blocking of the Cxcr4 receptor (Stumm et al., 2003; Borrell and Marin, 2006). This suggested that Cxcl12 signaling promotes CH-CRs chemotaxis. However, in vivo paradigms, in which a Cxcr4 antagonist was injected in utero in mouse embryonic forebrains, showed that CRs were present in the dorsal cortex but had derailed from the MZ. CRs were ectopically localized deep in the MZ and cortical plate, in contrast to the characteristic single-layer of CRs in control animals. Similar defects were observed when rat embryos were exposed in utero to a DNA-alkylating agent that triggers meningeal cell-death and results in a drastic downregulation of Cxcl12 (Paredes et al., 2006). Together, these studies suggested that Cxcl12/ Cxcr4 mediates CRs local chemoattraction to the meninges. In vivo analyses of mutant mice deficient in Cxcl12 and its receptors is consistent with this and shows that the degree of ectopic localization of CRs Developmental Neurobiology

14

Barber and Pierani

to be dependent on the stage and on the specific cortical territories analyzed (Stumm et al., 2003; Paredes et al., 2006; Borrell and Marin, 2006; Trousse et al., 2015). The most drastic defects were observed in E12 mutant embryos which lack the Cxcl122/2 ligand, in which CRs invaded the dorsal cortex, but were mislocalized deep in the cortical parenchyma throughout its rostral-caudal axis (Trousse et al., 2015) [Fig. 6(e)]. Analyses of Cxcr42/2 and Cxcr72/2 null mutant mice similarly showed CRs derailment from the MZ, however this occurred from midstages of corticogenesis (Borrell and Marin, 2006; Paredes et al., 2006; Trousse et al., 2015), suggesting that this pathway is not required for CRs initial tangential invasion of the cortex. Intriguingly, invalidation of Cxcr7 showed that CRs derailment occurred in a region specific manner that predominately corresponded to CH-CRs and PSB-CRs (Abe et al., 2014; Trousse et al., 2015) [Fig. 6(e)]. To address whether perturbation of both Cxcr4 and Cxcr7 receptors may recapitulate the earlier and more severe defects in CR positioning observed in Cxcl122/2 null mutants, Cxcr4 receptors were pharmacologically antagonized in Cxcr72/2 mutants (Trousse et al., 2015). Antagonizing both receptors resulted in the increased derailment of CRs from the MZ than when perturbing a single receptor alone, suggesting a possible compensatory function between these receptors in CH-CRs. Analysis of mutants in components of the Cxcl12 signaling pathway at E18 has shown CRs to be correctly positioned (Stumm et al., 2003). This suggests that there may be additional mechanisms, which could rescue CRs subpial positioning at later developmental stages. Thus together these studies show that CR subtypes differ in their response to Cxcl12, with Cxcr7, and both Cxcr4 and Cxcr7, being required for the correct superficial positioning of PSB-CRs and CH-CRs, respectively, during mid stages of corticogenesis. It remains unclear whether Cxcl12 is required for the MZ position of S-CRs or for CRs in the ventral telencephalon. Thus, in contrast to early in vitro experiments, this pathway does not appear to be essential for the vast majority of CRs initial tangential migration to the dorsal cortex in vivo. However, Cxcl122/2 and Cxcr42/2 null mutants show a similar reduction in total numbers of CRs (Stumm et al., 2003), suggesting that Cxcl12/Cxcr4 signaling could regulate the tangential invasion of, or play a role in the genesis of, a subset of CRs. Another interpretation is that mispositioned CRs may undergo cell death. The mechanisms by which Cxcl12 signaling maintains CRs subpial positions remain unknown; however, this pathway has been shown to confine cortical interDevelopmental Neurobiology

neurons to their tangential migratory streams (Stumm et al., 2003; Lopez-Bendito et al., 2008; Li et al., 2008a; Tanaka et al., 2010; Wang et al., 2011b; Lysko et al., 2011, 2014) by negatively modulating their leading process branching and their migration speeds through Cxcr4 and Cxcr7 receptors (Lysko et al., 2011; Wang et al., 2011b; Lysko et al., 2014). Cxcl12 could similarly influence CRs exploratory behavior or motility to maintain their streamlined positions at the cortical surface. Cxcr7 is expressed throughout the early PP and is maintained within the developing subplate layer at a time when this is downregulated in CRs (Trousse et al., 2015), suggesting that Cxcl12/Cxcr7 may play a role in the migration of, or in maintaining the positions of SPs within the forming PP and subplate.

Radial Glia Regulate CH-CRs Subpial Positions RGs have been shown to directly regulate CRs subpial positioning providing an additional mechanism to Cxcl12 signaling in this process (Kwon et al., 2011) [Fig. 6(d,f)]. Genetic invalidation studies assessed whether RG endfeet retraction could influence CRs positioning before reported defects in the pia basement membrane occur (Graus-Porta et al., 2001), by using the Emx1Cre mouse line (Gorski et al., 2002) to invalidate ß1-integrins at an earlier time point (E9.5) than previous studies [see above Fig. 6(d)]. The Emx1Cre mouse line targets cortical progenitors within the medial and dorsal pallial VZ (Gorski et al., 2002), corresponding to cortical territories CH-CRs and S-CRs invade at its surface (Bielle et al., 2005). Emx1Cre ablation of ß1-integrins resulted in a pronounced retraction of RG endfeet from the pia from E14.5, with no overt changes to the overlying pia, as assessed by laminin immunostaining. The mislocalization of RG endfeet closely correlated with CRs pial derailment both spatially and temporally. As Emx1 is also expressed in CH-CR and S-CR progenitors, the Wnt3aCre mouse line (Yoshida et al., 2006) was used to specifically target ß1-integrins in CH-CRs; however, this showed that CRs were correctly positioned in the MZ and thus suggesting that defects in CR derailment were not due to cell-autonomous ß1-integrins defects in CHCRs. A second conditional genetic strategy was also used to disrupt the proliferation of RG by removing Orc3, a protein complex essential for DNA replication from E13.5 (Kwon et al., 2011). This resulted in a severe loss of RG and gaps in the scaffold from E14.5, which correlated with CRs ectopic positions in the cortical plate without affecting the total


numbers of CRs generated, possibly because of the early generation of CRs and the perdurance of Orc3 protein prior to E13.5. While CR mispositioning was reported throughout the medial-lateral cortex it is unclear whether this occurred in a region-specific manner and, notably, whether CRs were misplaced in the rostral-medial cortex, which corresponds to regions populated by S-CRs at earlier stages. Indeed, to date, little is known on the mechanisms, which maintain S-CRs subpial positions. However, mice deficient in laminin ß2 and Ç3 isoforms show defects in the meninges and RG scaffold, with CRs displaced specifically in rostral and ventral-pallial territories (Radner et al., 2013), suggesting that RG may maintain the superficial positions of S-CRs and of CRs which invade the pir. The ß1-integrin deficient RG mutants exhibited a more pronounced CR displacement than Cxcr42/2, Cxcr72/2, or Cxcl122/2 mutants, with no changes in Cxcl12 expression in the meninges reported. This suggests that ß1-integrin signaling is an important mechanism, which maintains CRs subpial position independent to the Cxcr4/ Cxcr7/Cxcl12 pathway. While the molecular basis of CRs anchorage or interaction with RG endfeet remains unknown [Fig. 6(f)], RG endfeet are reported to contact migrating interneurons within the MZ (Yokota et al., 2007) and to guide axons in the developing retina (Bauch et al., 1998), with signaling molecules and receptors asymmetrically enriched within their basal endfeet (Lee and Cole, 2000; Yokota et al., 2010). Future studies should address the molecular mechanism by which RG confine CR subtypes to their strategic positions at the cortical surface.

CRs TANGENTIAL MIGRATION Transcriptional Regulation of Migration CR subtypes express different combinations of transcription factors, which regulate CR numbers and their cortical distributions, however to date, the direct transcriptional regulation of CR migration in vivo has not been studied. This is rendered difficult because these transcription factors play pleiotropic roles in CR development including: specifying CR progenitor domains (Foxg1, Dmrt5, Ascl1, Zic1,2,3, Lhx2), the number of CRs in specific cortical territories (Tbr1, Emx1/2, Pax6, Zic1-3, Ebf2/3, Lhx5, Lhx2; Nagai et al., 1997; Mallamaci et al., 2000a; Stoykova et al., 2000; Hevner et al., 2001; Shinozaki et al., 2002; Stoykova et al., 2003; Muzio and Mallamaci, 2003; Hanashima et al., 2007; Inoue et al., 2008; Shibata et al., 2008; Saulnier et al., 2013; Dixit et al., 2011;

15

Chiara et al., 2012; Roy et al., 2014), and in promoting CR survival (p73) (Tissir et al., 2009). Analysis of hypomorphic Zic2 mutants and Zic1-3 null mutants (Nagai et al., 2000; Inoue et al., 2007, 2008), for example, show that Zic1-3 regulate CR numbers in the rostral and intermediate cortex by specifying S and dorsal CH progenitor domains required for the correct generation of S-CRs and CH-CRs. Tbr1 is expressed soon after cortical progenitors differentiate and in early postmitotic CRs (Bulfone et al., 1995). Knockout mice, in which the DNA-binding domain of Tbr1 was targeted, showed that Tbr1 is required for maintaining the correct molecular differentiation of CRs in the lateral and rostral cortex and promoted Reelin expression (Hevner et al., 2001). This is consistent with reports that Tbr1 directly binds to the Reelin promoter (Chen et al., 2002). Reelin and Calretinin expression in the medial cortex was not affected raising the question as to whether there are subtype-specific differences in the requirement of Tbr1 for CR differentiation. The Emx homeobox and the Pax6 genes exert a positive and negative regulatory effect on the number of CRs in the cortex, respectively (Chapouton et al., 1999; Mallamaci et al., 2000a; Shinozaki et al., 2002; Bishop et al., 2003; Stoykova et al., 2003). Emx1/ Emx2 are expressed in overlapping patterns, and in an opposing gradient to Pax6 in the cortical neuroepithelium (Simeone et al., 1992; Gulisano et al., 1996; Mallamaci et al., 2000b; Cecchi and Boncinelli, 2000; Bishop et al., 2003; Mallamaci and Stoykova, 2006), and have crucial roles in cortical patterning, proliferation, neuronal differentiation, cortical lamination, and axon-guidance (Gotz et al., 1998; Mallamaci et al., 2000b; Stoykova et al., 2000; Shinozaki et al., 2002; Bishop et al., 2003). Postmitotic CRs also express Emx2 (Shinozaki et al., 2002), and subsets also express Pax6 at low levels (Stoykova et al., 2003). Emx22/2 null mutants show that CR development is initially normal, but that Reelin1 Calretinin1 CRs are lost in the lateral and dorsal cortex from mid corticogenesis, with a complete absence of CR markers observed in Emx12/2Emx22/2 double mutants. Despite the drastic loss of CRs, cortical progenitor proliferation was reported to be close to normal, with no signs of premature precursor differentiation or altered apoptosis in either single or double mutants. Birth-dating studies suggested that CRs were correctly generated but subsequently scattered from the PP and failed to express their appropriate CR markers. Thus Emx1/2 appear to be important for the correct differentiation of CRs and the maintenance of their molecular identities (Mallamaci et al., 2000a; Shinozaki et al., 2002; Bishop et al., 2003). In contrast, analysis Developmental Neurobiology

16

Barber and Pierani

of sey mutant mice, which are deficient in the Pax6 transcription factor, show an opposite and striking increase in CRs within the rostral and lateral cortex (Stoykova et al., 2003). These corresponds to regions where Pax6 is strongly expressed (Bishop et al., 2003; Muzio and Mallamaci, 2003) and is consistent with Pax6 being crucial for neurogenesis (Gotz et al., 1998; Warren et al., 1999; Berger et al., 2007a; Quinn et al., 2007). Consistent with this are the observations of an accelerated proliferation and enlarged cortical VZ observed in sey mutants (Stoykova et al., 2003). However, experiments, which analyzed proliferation in cultured cortical explants from Pax6 sey mice showed there were no differences in CRs generated relative to controls (Stoykova et al., 2003). It is important to note that these experiments were carried out at a time when CRs were thought to predominately originate in the neocortical VZ, and so it is unclear whether the cortical explants included CR sources, which are located at the pallial borders. An increased number of Emx2expressing CRs in the rostral cortex, and of Calretinin1Reelin1 subtypes in the pir was also reported, suggesting a shift in the molecular identity of CRs within the Pax6-deficient MZ (Stoykova et al., 2003). Thus, another interpretation of these studies is the expansion of sources of Emx2-expressing CRs, possibly deriving from the hem source, and/or a misspecification of CRs in the absence of Pax6, which is consistent with its cross-regulatory interactions with the Emx1/2 genes. Moreover, Pax6 may be important for the generation and specification of CRs, which invade the rostral and lateral cortex, and likely derive from the septum and PSB. Both Emx and Pax6 genes were shown to have a noncell-autonomous effect on migration. DiI labeling studies of the ganglionic eminence in Emx22/2 and Emx12/2Emx22/2 mutants showed a delayed and complete impairment in the migration of cells to the cortex, respectively. As Emx1 is not expressed in the subpallium (Tole et al., 2000), this suggested a noncell-autonomous mechanism (Shinozaki et al., 2002). In agreement with this, transplantation experiments showed that Emx1/Emx2 double mutant cells from the ganglionic eminences migrated to the wildtype cortex, whereas wildtype cells failed to migrate in the mutant cortex. In contrast, the ventral to dorsal migration of cortical interneurons is enhanced in Pax6 mutants (Chapouton et al., 1999), suggesting that the PSB is more permeable to tangentially migrating cells from extraneocortical sources. Indeed, transplant studies showed a greater influx of wildtype ganglionic eminence cells to the Pax6deficient dorsal cortex compared with the wildtype environments (Mallamaci et al., 2000a; Shinozaki Developmental Neurobiology

et al., 2002). Given that Emx1/2 and Pax6 function in the cortex appears essential for the correct influx of cells migrating from the ganglionic eminences, it would be interesting to address whether the tangential migration of PSB-CRs is also affected and could contribute to the loss or accumulation of CRs observed in the lateral cortex in Emx12/2Emx22/2 and Pax62/2 mutants, respectively. Tracing studies in the Pax6 sey deficient cortex at earlier stages has shown that CHCRs migration is disordered; they change their overall direction in migration and transgress the ventral pallium unlike in the control environments. This is consistent with the PSB being more permeable upon Pax6 deficiency. Hem explants transplanted into the lateral ganglionic eminence (LGE) have also shown that CHCHs invaded the dorsal cortex in Pax6-deficient mice, but not in the wildtype cortex (Ceci et al., 2010). Together, these experiments suggested non-cellautonomous mechanisms in CR migration, which may be secondary to patterning defects in the PSB in both Emx1/2 and Pax6 mutants (Stoykova et al., 2000; Toresson et al., 2000; Yun et al., 2001). Several genes are upregulated in the Pax6-deficient cortex, including Cxcl12 (Ceci et al., 2010), which could promote CRs motility as shown for cortical interneurons (Lysko et al., 2011; Wang et al., 2011b; Lysko et al., 2014) and enhance CRs tangential invasion of the cortex. Thus, together, these studies show that Emx1/2 and Pax6 have opposing effects on regulating the number of CRs in the cortex through promoting the correct differentiation and maintenance of CRs molecular identity, as well as pointing toward possible noncell-autonomous roles in regulating CR migration, likely through their patterning of cortical territories. In addition, a role for members of the early B cell factor, Ebf, transcription factors (Miquelajauregui et al., 2010; Chiara et al., 2012), and the LIMhomeodomain transcription factor LHX5 (Miquelajauregui et al., 2010) in CRs migration has been suggested (Fig. 7). Ebf genes regulate regional specification, neuronal differentiation (Garel et al., 1999, 1997; Garcia-Dominguez et al., 2003), axonguidance (Garel et al., 2002), and neuronal migration in the developing nervous system (Garel et al., 2000; Corradi et al., 2003; Croci et al., 2006). Ebf2/3 gene members are expressed in p731 S and CH-CR sources and in their postmitotic subtypes, Ebf3 in the PSB source, and Ebf1 suggested to be expressed in postmitotic PSB-CRs and in CRs, which have reached the dorsal cortex (Yamazaki et al., 2004; Hanashima et al., 2007; Chowdhury et al., 2010; Chuang et al., 2011; Chiara et al., 2012), suggesting a potential role for Ebf genes in the generation,


specification, and migration of CR subtypes. Analysis of Ebf22/2 null mice has shown a transient change in the distribution of CR subtypes along the mediallateral axis of the caudal cortex, which suggested a delay in the migration of CRs from the hem (Chiara et al., 2012). This was consistent with in vitro analysis of CH-CRs migratory behaviors in laminin stripe assays, which showed that overexpression or knockdown of both Ebf2/Ebf3 promoted or impaired CHCRs chemotactic migration, respectively (Chiara et al., 2012). Impairing the activity of both Ebf2/3 and Ebf1/2/3 genes simultaneously, resulted in a greater deficiency in migration than when impairing single Ebf genes in CH-CRs, suggesting Ebf genes act in concert to regulate migration. In addition to the suggested CH-CR migration defects, Ebf2 mutant mice showed an upregulation of Ebf3 and ventral expansion of Wnt3a in the hem, and a transient increased proliferation in the hem (Chiara et al., 2012). Dbx1 and Ebf3 were also downregulated in the septum in the Ebf2 knockouts/mutants, which correlated with the reduction of S-CRs. These observations suggest that Ebf2 may regulate the generation and/or specification of CH-CRs and S-CRs through the regulation of Wnt3a and Dbx1, respectively. Strikingly, a noncell-autonomous upregulation of Ebf3 and Dbx1 was observed in the PSB, which correlated with the increased accumulation of Ebf31Reelin1 CRs in the lateral pallium, suggesting additional noncell autonomous effects of Ebf2 on the generation and possibly migration of PSB-CR subtypes. Thus, these studies suggest a role for Ebf2 in the generation of CR subtypes, and the migration of CH-CRs. While the mechanisms by which Ebf genes could regulate CH-CR migration remain unknown, they have been shown to regulate the expression of cellmembrane proteins, cell-adhesive interactions, and migration in other cell-types. Ectopic expression of Ebf1 in chick spinal cord and hindbrain progenitors, results in a precocious differentiation and migration of neurons to the mantle layer, through the downregulation of the progenitor-associated N-cadherin celladhesion molecule and the activation of R-cadherin (Garcia-Dominguez et al., 2003). Ebf2-deficient gonadotropin releasing hormone-synthesizing neurons also show a severe impairment in their tangential migration and remain abnormally clustered close to their source where they exhibit defective polarized morphologies (Corradi et al., 2003). This suggests that Ebf genes may regulate downstream target genes, which initiate cell polarization and control the expression of cell-adhesion molecules required to initiate cell migration (Garcia-Dominguez et al., 2003). This is relevant as CRs have been suggested to

17

migrate by contact-dependent interactions (VillarCervino et al., 2013) and to express R-cadherin (Yamazaki et al., 2004). Cxcr4 expression was also decreased in CH-CRs in Ebf22/2 null mutants with no changes reported in the meninges-derived Cxcl12 (Chiara et al., 2012), suggesting that Ebf genes may be upstream of Cxcr4, and thus regulate CH-CR’s response to Cxcl12 and possibly their MZ position. All together, these studies suggest that Ebfs might play a role in the generation, specification and migration of CRs, however whether this regulation is direct or indirect on any or all of these steps during CRs development remains to be addressed. The LIM homeodomain transcription factors (Lhx) are expressed in the cerebral cortex (Retaux et al., 1999; Bulchand et al., 2003; Alifragis et al., 2004; Yamazaki et al., 2004), where these act in a combinatorial manner to specify cellular and regional identity (Bulchand et al., 2001). Lhx6 has been shown to regulate cortical interneurons tangential migration (Alifragis et al., 2004), and Lhx5 appears to be upstream of Ebf2 genes (Miquelajauregui et al., 2010). Lhx1/Lhx5 genes are expressed in the CR sources of the Eth, S, and hem, and in postmitotic CRs throughout the MZ, with Lhx5 also expressed in the ventral caudomedial telencephalic wall (vCMTW), possibly corresponding to CR cells migrating from the Eth. The vCMTW is a suggested source of CRs, which migrate to the pir (Abellan et al., 2010a; Miquelajauregui et al., 2010). Analysis of Lhx52/2 null mutant mice showed that in addition to patterning and specification defects of midline structures, there was a drastic reduction of CR markers (Reelin, p73, Lhx1, p21, and Ebf2) in CR sources and throughout the neocortical MZ and pir (Miquelajauregui et al., 2010), suggesting that Lhx5 is important for at least the correct differentiation of vCMTW and/or septum-derived CRs and their normal distributions. While possible defects in CR generation were not addressed, tracer-dye injections into the mutant cortical hem showed that CH-CRs migration was inhibited and that this correlated with a downregulation of Ebf2, consistent with the delayed migration observed in Ebf22/2 null mice (Chiara et al., 2012). This suggested that Lhx5 may be upstream of Ebf2 and that CH-CRs migration may be impaired. Tracer injections in the misspecified vCMTW, also showed this gave rise to CR cells expressing p73, Reelin, Ebf2, and Lhx1, which aberrantly migrated to form ectopic clusters in the caudal cortex (Miquelajauregui et al., 2010). This suggested that the aberrant migratory behaviors could be due to the misspecification and altered intrinsic properties of CRs, including potential defects in their crossDevelopmental Neurobiology

18

Barber and Pierani

repulsive inhibitory or cell-adhesive interactions; or that this may reflect non-cell-autonomous defects in the caudal cortex due to loss of midline cortical hem and choroid plexus territories. Whether Lhx5 also plays a role in S-CR migration has not been addressed; however, this could contribute to the reduction of CRs in the neocortex in Lhx5 mutants. Cellular ectopias have also been observed in mice deficient in p73, Zic1,2,3, Emx2, and Tbr1 genes (Hevner et al., 2001, 2003; Shinozaki et al., 2002; Meyer et al., 2004; Inoue et al., 2008), which may also reflect a more subtle defect in their differentiation or specification, which could impair their celladhesive or contact-dependent migratory properties. Thus together, these studies show that transcription factors regulate various steps in CR development which are crucial in regulating their numbers and distributions, with a possible cell-autonomous role for Ebf2/3 and Lhx5 in regulating CR migration, and a possible role for Pax6 and Emx1/2 in the noncellautonomous regulation of CR migration in vivo. Given that, it is difficult to discriminate a defect in cell migration from changes in CR generation, future experiments are required to address how transcription factors intrinsically specify CR migratory behaviors. This will be facilitated when their downstream target genes are identified, and through conditional and temporally regulated genetic invalidation studies. SPs express several transcription factors similar to CRs including Pax6 (Stoykova et al., 2003), Emx1(Shinozaki et al., 2002), Ebf2 (Chiara et al., 2012), and Tbr1 (Hevner et al., 2001), which have all been shown to positively regulate SP numbers in the cortex. Most of these genes are necessary for the correct differentiation and maintenance of SPs molecular properties (Tbr1, Pax6, Emx1/2); however, aberrant multipolar migration from the neocortical VZ has also been reported in Tbr1-deficient mice (Tabata and Nakajima, 2003) with Ebf2 shown to be important for the radial migration of Purkinje cerebellar neurons (Zhao et al., 2007) suggesting that these transcription factors could regulate SPs radial migration. While Emx2 is not expressed in postmitotic SPs (Gulisano et al., 1996; Bishop et al., 2003) mice deficient in Emx2 show a reduction in SPs in the caudal and medial cortex, with a complete absence of SPs throughout the cortex in Emx1/2 double mutants (Shinozaki et al., 2002). The absence of medial pallial structures in Emx1/2, may explain a loss of SPs migrating from the RMTW; however, no major defects in proliferation were reported in remaining neocortical germinal territories, which give rise to radially migrating SPs, raising the question as to whether there are additional noncell-autonomous Developmental Neurobiology

defects in SPs radial migration in these mutants. Retroviral injection labeling studies have also shown the defective radial migration of neurons from the cortical VZ in Pax6 mutants (Chapouton et al., 1999), probably due to defects in the radial glia (Gotz et al., 1998), suggesting Pax6 may be important in the generation and radial migration of populations of Calretinin1 SPs. However, as for CRs, further studies should shed light on how transcription factors regulate SPs development, and further, whether similar mechanisms underlie both SPs and CRs generation and migration.

Extrinsic Regulation of CR Migration: Guidance Cues The above studies suggested that the regional patterning of cortical territories may non-cell-autonomously influence CR migration, suggesting that extrinsic guidance cues may exist in the cortex. Indeed, fluorescent-dye labeling studies in cortical slices and in whole embryos exo-utero have shown that CHCRs migrate along highly directional trajectories, following caudal-medial to rostral-lateral trajectories with little mixing of adjacent streams, and not populating the subpallium (Garcia-Moreno et al., 2007; Ceci et al., 2010). Studies, which heterotypically transplanted cortical hem explants to different rostral-caudal levels, showed that CH-CRs adopted a new migratory path and did not transgress the PSB (Ceci et al., 2010). Genetic tracing studies have also shown that molecularly distinct subtypes follow directed and opposing routes to invade complementary territories at the cortical surface (Bielle et al., 2005). It was therefore possible that extrinsic guidance cues may be segregated in the cortical parenchyma, which guide and delimit CRs migration. Surprisingly, experiments in which the meninges was dissected from distinct cortical regions, and cocultured with CH explants at E12.5, showed there were no regional differences in their chemoattraction, which argued against the existence of gradients of secreted guidance cues in the meninges or underlying cortical parenchyma (Borrell and Marin, 2006). Further, CH-explants transplanted either into the dorsal cortex or in the LGE in E12.5 cortical slice cultures showed that CH-CRs dispersed equally in all directions along the cortical surface, suggesting that the meninges was an equally permissive migratory substrate and that guidance cues were absent (Borrell and Marin, 2006). It is interesting to note that when hem explants were transplanted into the LGE one day earlier, their derived CRs did not migrate dorsally to invade the dorsal cortex (Ceci et al., 2010), raising


the speculative possibility that a lack of attractive/or presence of repulsive guidance cues may exist at earlier time points. Furthermore, since all the above experiments studied the properties of hem-derived CRs at a precise developmental stage, it is possible that guidance cues might exist for other CR subtypes or at earlier stages.

Eph/Ephrins-Mediated ContactRepulsion of CRs CRs have been suggested to tangentially invade the cortex by contact inhibition of locomotion (CIL)/contact-repulsion (Borrell and Marin, 2006; VillarCervino et al., 2013), a mode of migration first described by Abercombie and others. This mode of migration was based on observations of colliding fibroblasts in chick heart explant confrontation assays. These showed that when colliding fibroblasts came into contact with another cell they stopped migrating in the direction which produced a collision with another cell. Upon cell contact they retracted their protrusions and repolarized to extend a new protrusion from a different point along their cell perimeter, to change their direction of migration away from the point of cell-cell contact (Abercrombie and Heaysman, 1953, 1954; Abercrombie and Ambrose, 1958). Moreover, colliding cells never occupied the same space and did not migrate on top of each other. This stochastic mechanism of migration resulted in cells dispersing from regions of high concentration to low concentration, without the need for exogenous guidance cues. This has also been shown to be a mechanism by which neural crest cells and macrophages migrate in a directional manner in vivo (Carmona-Fontaine et al., 2008; Stramer et al., 2010; Davis et al., 2012). Confrontation assays of cortical hem explants in vitro showed that CRs migrated shorter distances toward the confronted explant than away from it, and did not migrate past the midpoint between the two explants, first suggesting that CHCRs migration was impaired by neighboring cells (Borrell and Marin, 2006). It was suggested that CRs disperse from the hem and throughout the cortical surface by contact-inhibitory interactions with adjacent CRs. This was consistent with the observation that in vivo the depletion of a CR subpopulation from a cortical territory, resulted in its repopulation by CR subtypes from other sources (Bielle et al., 2005; Griveau et al., 2010). Live-imaging studies have confirmed that CRs follow random trajectories and are repelled upon contact with adjacent cells when migrating on 2-d substrates in vitro. Contact with a neighboring CR results in the collapse and retraction

19

of their leading process and in a change in their direction of migration (Villar-Cervino et al., 2013). These experiments showed that, similar to other cells, which undergo contact-repulsion, these exhibited low persistence in directionality and increased velocity following cell-contact. The observation that confronted CR explants taken from distinct CR sources resulted in similar heterotypic contact-repulsive interactions, has suggested that contact-repulsion is a common mechanism by which all CR subtypes disperse from their sources to invade the cortex, without the need for extrinsic guidance cues (Villar-Cervino et al., 2013). This study also showed that a proportion of CRs migrated by random-walking and change their direction of migration without contacting a neighboring cell, however this was found to result in less pronounced changes in their direction of migration and mathematical modeling predicted this was a less efficient mechanism of dispersion (Villar-Cervino et al., 2013). Thus, mathematical modeling and in vitro migration studies predicted that contact-repulsion promoted CRs efficient dispersion and coverage of cortical territories, and maintained their preferential distributions. However, further studies are needed to address the relevance and relative weight of random walking and contact-repulsion in the migration of CRs in vivo in a 3-D rather than a 2-D environment where contact-repulsion behaviors may be favored for non-transformed cells. At the molecular level, contact-repulsion was shown to be mediated by Ephrin receptors and their membrane-bound ephrin ligands (Villar-Cervino et al., 2013; Fig. 7). Ephrin receptors are the largest subfamily of transmembrane tyrosine kinases (Klein, 2012) which mediate repulsion during growth cone retraction in developing axons and during cell migration (Wilkinson, 2001). Importantly, ephrin signaling can transduce signals in both the receptor-bearing and ligand-bearing cell (Cowan and Henkemeyer, 2002; Egea and Klein, 2007), and CRs express several Eph receptors and ligands of the A and B subclasses during their migration (E10.5-12.5; VillarCervino et al., 2013). Abrogating Eph/ephrin signaling in CRs in vitro has shown this increased CRs persistence in directionality, the time which CR cells remained in contact, and reduced their contactrepulsive interactions. Consistent with these in vitro observations, analysis of triple EphB1/B2/B3 mutants showed a depletion of CRs in vivo which was especially severe in the caudal E12.5 cortex, with rostral and lateral cortical territories less affected (VillarCervino et al., 2013). While the molecular identity of CR subtypes was not characterized in these mutants, the caudal cortex corresponds to a region Developmental Neurobiology

20

Barber and Pierani

Figure 8 Convergence of molecular pathways that regulate CRs subpial positioning and tangential migration. (a, b) Summaries of ligand-transmembrane receptor signalling pathways activated in CRs, which regulate their local chemoattraction to the pia (CXCL12/CXCR4/CXCR7), promotes the remodelling of the F-actin cytoskeleton required for CRs exploratory behavior and cell motility (Sema3E/PlexinD1), and mediates their contact-repulsive interactions and dispersion [Eph receptors (EphB/EphA) and ephrin ligands (ephrinA/ephrinB)]. Note Sema3E/PlexinD1 signalling negatively modulates CXCL12/CXCR4 intracellular signalling by converging on ERK1/2. Receptors and signalling pathways which are known to converge and regulate migration in other cell types, and which may have a similar role in migrating CRs, are shown in gray in a-b.

predominantly populated by CRs from the hem at embryonic stages raising the speculation that, in vivo, EphB1/B2/B3/ephrins-mediated contact-repulsion may be especially crucial for CH-CRs migration. Eph/ephrins have also been shown to promote the proliferation of cortical progenitor cells (North et al., 2009), to inhibit neuronal differentiation during corticogenesis (Qiu et al., 2008), as well to regulate proliferation and differentiation within neurogenic regions in the adult cerebral cortex (Conover et al., 2000; Holmberg et al., 2005; Jiao et al., 2008; Khodosevich et al., 2011). It therefore remains to be shown how potential changes in CR genesis may contribute to the observed CR phenotype within the cortex of triple EphB1/EphB2/EphB3 mutants. Eph/ephrin signaling has also been shown to converge with other signaling pathways (Fig. 8) which could offer an explanation as to why regional differences in CR numbers were observed in EphB1/B2/B3 mutants in vivo. Eph/ephrins modulate integrindependent cell-adhesive interactions with the extracellular matrix to promote or inhibit migration in diverse cell-types (Dulabon et al., 2000; Luque, 2004). This would be expected to be important during CRs migration, given that they migrate along the matrix-protein rich pia [Fig. 8(a)]. The observation that gradients of laminin isoforms exist in the pia Developmental Neurobiology

membrane (Li et al., 2012; Radner et al., 2013) suggests this could differentially influence CRs adhesive interactions and motility in a region-specific manner in the cortex. EphB2 and EphB4 activation was also shown to enhance Cxcl12-induced endothelial cell chemotaxis, by synergistically activating downstream serine/threonine protein kinase B (AKT) and regulating their adhesive matrix-protein interactions (Salvucci et al., 2006). EphrinB reverse signaling in the ligand-bearing cell was conversely shown to inhibit the Cxcl12-induced chemotaxis of cerebellar granule cells through a cytoplasmic protein, which inhibits G-protein signaling (Lu et al., 2001), suggesting that Eph/ephrins could modulate CRs response to Cxcl12 signaling [Fig. 8(b)]. Whether these signaling pathways converge to modulate CRs contactinhibitory interactions and dispersion remains to be investigated.

Negative Modulation of CRs Motility by Sema3E/PlexinD1 and Vamp3 Recently, timelapse analysis of whole flattened cortical preparations combined with genetic tracing of SCR, CH-CR, and PSB-CR subtypes has suggested that CR subtypes exhibit differences in their onset of migration, direction of migration, speed, and


directionality (Barber et al., 2015). Using mathematical models generated from time-lapse experimental data, this study predicted that differences in CR subtypes migration speed and persistence in directionality, were the primary migration parameters affecting CR subtypes differential distribution and dispersion in cortical territories (Barber et al., 2015). Indeed, to date, two different pathways have been identified which negatively modulate CRs motility and migration speed, the Semaphorin/PlexinD1 pathway and the vesicular trafficking protein Vamp3. Semaphorins are a major class of secreted or membrane-bound guidance cues, best known for their chemotropic role in axon guidance and vascular development (Luo et al., 1993; Chen et al., 1998b; Bagri and Tessier-Lavigne, 2002; Gu et al., 2005; Oh and Gu, 2013; Gu and Giraudo, 2013; Bussolino et al., 2014). The class III members of secreted semaphorins (Sema3E, Sema3D, Sema3A) have crucial roles in axon guidance, cancer metastasis and cell migration (Chen et al., 1998a; Kerjan et al., 2005; Chauvet et al., 2007; Casazza et al., 2010; Aghajanian et al., 2014; Mendes-da-Cruz et al., 2014), and signal through heterocomplexes of ligand-binding neuropilin receptors and their signal transducing plexin co-receptors (Winberg et al., 1998a,b; Takahashi et al., 1999; Bagri and Tessier-Lavigne, 2002; Yaron et al., 2005; Janssen et al., 2012; Demyanenko et al., 2014). Semaphorins mediate chemorepulsion or chemoattraction during interneuron migration and axon guidance, depending on the specific semaphorin member (Marin et al., 2001; Bagri and TessierLavigne, 2002; Tamamaki et al., 2003; Toyofuku et al., 2008), or on the composition of receptor heterocomplexes these bind and signal through (Chauvet et al., 2007; Hernandez-Miranda et al., 2011; Andrews et al., 2013). Sema3E, which mediates repulsion in axon-guidance and in the vascular system (Gu et al., 2005; Chauvet et al., 2007), was shown to regulate CR migration from the hem by signaling through PlexinD1 receptors (Bribian et al., 2014). Sema3E was shown to be expressed in the neocortical parenchyma from E12.5-E13.5 in a caudal-medial to lateral gradient, and to complement PlexinD1 expression in CH-CRs, which migrate from the hem (Fig. 7). However, whereas semaphorins provide directional guidance during interneuron migration and axon-growth (Marin et al., 2001; Bagri and Tessier-Lavigne, 2002; Tamamaki et al., 2003), this study found that impairing PlexinD1 or Sema3E signaling activity in hem explant assays in vitro did not affect CH-CRs direction of migration, but modulated their motility (Bribian et al., 2014).These in vitro observations were confirmed in in-vivo para-

21

digms in which cortical hem explants transplanted into Sema3E-deficient cortical slices resulted in the enhanced dispersion and tangential invasion of the cortex by CH-CRs, consistent with endogenous Sema3E negatively regulates CH-CRs dispersion in vivo. The hem transplant studies were carried out at E13.5, corresponding to a time point when the surface of the embryonic cerebral cortex is covered by Reelin1 CR cells (Takiguchi-Hayashi et al., 2004; Yoshida et al., 2006; Tissir et al., 2009; VillarCervino et al., 2013), and when cell density and contact-dependent interactions are high, suggesting that contact-repulsion alone is insufficient to restrict CH-CRs dispersion in cortical territories. The in vivo analysis of PlexinD1-deficient mice, further showed an increased accumulation of CRs within the dorsal cortex, suggesting a precocious invasion of CH-CRs in the cortex and consistent with Sema3E/PlexinD1 negatively modulating CH-CRs motility. This suggests that Sema3E signaling is necessary to restrict the extent of CH-CRs dispersion in cortical territories in addition to contact-dependent interactions. Timelapse analysis of PlexinD1-deficient CH-CRs showed their reduced migration speed was in part explained by their enlarged leading neurites and decreased number of protrusions. This was consistent with PlexinD1’s known GTPase-activating protein (GAP) activity, which negatively modulates the signal transducing Rho GTPases. The latter are required to remodel the F-actin cytoskeleton (Etienne-Manneville and Hall, 2002; Negishi and Katoh, 2002; Gay et al., 2011) which underlies the formation of F-actin rich membrane ruffles and protrusions at a cell migratory edge, that are crucial to initiate cell motility and migration. In addition, biochemical experiments showed that Sema3E/PlexinD1 acted in parallel and modulated Cxcl12/Cxcr4 signaling. Sema3E was shown to delay the onset of ERK1/2 signaling, which is activated downstream of Cxcr4 (Ryu et al., 2010; Bribian et al., 2014), thereby negatively modulating CRs response to Cxcl12 [Fig. 8(a)]. In addition, Sema3E was found to potentiate Cxcl12-induced phosphorylation of ADF/Cofilin [Fig. 8(a)]. ADF/ Cofilin is a ubiquitous actin-binding protein, which is essential for the depolymerization of actin filaments and actin-based protrusions (Arber et al., 1998), and was consistent with the decreased exploratory behavior observed in PlexinD1-deficient CH-CRs. The delay in both ERK1/2 activation and ADF/Cofilin signaling was shown to be mediated through PlexinD1’s GAP activity. However, Sema3E has also been shown to inhibit proliferation in other cell-types (Movassagh et al., 2014) raising the possibility that this pathway may additionally impact CR generation. Developmental Neurobiology

22

Barber and Pierani

While an additional role for Sema3E/PlexinD1 in CR generation remains to be addressed in vivo, analysis of hem explants in vitro suggested that Sema3E does not affect proliferation or apoptosis (Bribian et al., 2014). Thus, together, this study strongly suggests an endogenous role for PlexinD1/Sema3E in negatively regulating CH-CRs migration speed and motility in vivo. Sema3E/PlexinD1 is reported to modulate thymocytes’ integrin ß1-dependent adhesion to laminin, with a deficiency in PlexinD1 or the addition of Sema3E shown to reduce the binding strength and stability of ß1 integrin interactions to laminin, respectively, thereby enhancing thymocytes migration (Choi et al., 2014). Whether this pathway also influences CRs motility through modulating their interactions with the pia basement membrane or RG endfeet should be addressed in future studies. Sema3E is expressed in a caudal-medial to lateral gradient within the cortical neuroepithelium, and while the cellular source of Sema3E expression has not been identified, this is consistent with Sema3E being secreted by RGs and with their reported interactions with CRs (Kwon et al., 2011). Sema3E is also expressed in RGs in the LGE and Sema5A in the PSB (Medina et al., 2004; Ceci et al., 2010), which is interesting as the ventral pallium corresponds to a region which CH-CRs do not transgress in tracer labeling experiments at early stages (Ceci et al., 2010). This raises the possibility that Sema3E may contribute to the dorsal-lateral and lateral restriction of CH-CRS and PSB-CRs, respectively, and prevent CH-CRs migrating into the ventral pallium. Finally, PlexinB subfamily members have also been shown to promote neurite outgrowth through their homophillic interactions (Hartwig et al., 2005), raising the possibility that PlexinD1 may also play a role in CRs contact-dependent interactions (Villar-Cervino et al., 2013). Vesicle-associated membrane proteins, also known as vesicular SNAREs (N-ethylmaleimide sensitive factor attachment protein receptor), have a crucial role in mediating the docking and fusion of secretory vesicles during exocytosis through their interaction with cognate t-SNAREs, which are localized at a cell’s plasma membrane (Proux-Gillardeaux et al., 2005b). VAMP3 is classically known as the non-neuronal member due to its high expression in non-neuronal cells in the mature brain (Chilcote et al., 1995), where this has an essential role in the exocytosis of recycling endosomes (Galli et al., 1994) and in promoting the motility of epithelial cells and macrophages through integrin receptor recycling (Proux-Gillardeaux et al., 2005a; Skalski et al., 2010; Veale et al., 2010, 2011; Riggs et al., 2012). S-CR and CH-CRs were recently shown to strongly express Vamp3 and its role in CR migraDevelopmental Neurobiology

tion was investigated (Barber et al., 2015). This study selectively cleaved and inactivated VAMP1-3 members in migrating S-CRs and CH-CRs (Barber et al., 2015), using transgenic mice that allowed for Cre recombinase-dependent expression of the botulinum neurotoxin B (BoNT/B) (iBot-mutants; Chilcote et al., 1995; Slezak et al., 2012), and their migration analysed by timelapse microscopy. Imaging of whole flattened cerebral cortices showed that abrogating VAMP3 resulted in S-CR and CH-CRs faster migration speeds but did not alter their directionality index, showing that VAMP1-3-dependent vesicular trafficking negatively modulates the motility of S-CRs and CH-CRs, by specifically regulating their migration speed in a cell-autonomous manner. Analysis of these conditional mutants in vivo showed that S-CRs and CH-CRs faster migration speeds was consistent with their redistribution in more distant cortical territories. Analysis of VAMP3 null mutants further showed a similar ectopic accumulation of CR subtypes to the iBot mutants suggesting that VAMP3 was primarily responsible for S-CRs faster migration speeds. The observation that VAMP3 specifically modulated CR subtypes migration speed but did not affect their directionality was reciprocal to studies in which Ephrin/ Eph signaling was abrogated. This specifically perturbed contact-repulsive interactions between CRs and resulted in their increased directionality index in vitro, without affecting their migration speed and general motility (Villar-Cervino et al., 2013). Thus, it appears that directionality and speed of migration may be independently controlled by distinct molecular pathways, likely involving Ephrins/Eph-mediated contactrepulsion and Sema/PlexinD1/VAMP3-mediated vesicular trafficking, respectively. Indeed, the increased dispersion of CRs in Vamp3 null and conditional Ibot mutants is similar to that reported in PlexinD1 null mice in vivo (Bribian et al., 2014). This is especially relevant, given that VAMP2-dependent vesicular trafficking of PlexinA1/Neuropilin1 receptors has been shown to underlie Sema3A-dependent repulsion during axon guidance (Zylbersztejn et al., 2012), and raises the possibility that defects in VAMP3-dependent recycling of PlexinD1 receptors could impair CH-CRs response to Sema3E and mediate the faster migration speed and redistribution in Vamp3 and iBot mutants [Fig. 8(a)].

MIGRATION AND CORTICAL PATTERNING To date, two distinct mechanisms have been identified which maintain CR subtypes subpial positions,


the chemokine Cxcl12/Cxcr4/Cxcr7 signaling pathway, and the interaction of CRs with RGs endfeet (Stumm et al., 2003; Borrell and Marin, 2006; Paredes et al., 2006; Kwon et al., 2011; Trousse et al., 2015). CRs confinement at the cortical surface is crucial for CRs signaling activities, best illustrated by the requirement of a superficial Reelin source for the somal translocation of projection neurons and the correct inside-out formation of cortical layers (Ogawa et al., 1995; D’Arcangelo et al., 1997; Magdaleno et al., 2002; Franco et al., 2011; Sekine et al., 2011; Gil-Sanz et al., 2013). In addition, this facilitates CRs direct homophillic and heterophillic interactions with the leading processes of pyramidal neurons in the MZ during their terminal phases of migration (Franco et al., 2011; Gil-Sanz et al., 2013). Moreover, the potential anchorage of CRs to RG endfeet (Kwon et al., 2011) provides a mechanism by which CRs can directly signal to RG progenitors through both secreted or contact-dependent cues, and is consistent with observations that changes in CRs composition at the cortical surface influences both RGs mode of cell division as well as their generation of intermediate progenitors (Griveau et al., 2010). CRs superficial localization and enrichment of morphogens could also potentially generate asymmetric basal-apical signaling in RGs, and further, contribute to spatially distinct signaling niches to the deeply positioned intermediate progenitors. Another striking feature of CR subtypes migration is their invasion of complementary cortical territories, which has been shown to influence the early patterning of the cortex (Griveau et al., 2010). CRs dispersion in the cortex has been shown to be mediated through Eph/Ephrin contact-repulsive interactions, with CRs overall direction of dispersion in the cortex stochastically determined in response to cell density (VillarCervino et al., 2013). However, Sema/PlexinD1 and VAMP3 signaling appears to provide additional mechanisms by which CH-CRs and S-CRs motility and extent of dispersion in cortical territories is tightly regulated (Bribian et al., 2014; Barber et al., 2015), suggesting there is subtype-specific regulation of invasion of cortical territories. This is especially significant given that CR subtypes have been shown to be differentially enriched in morphogens and to act as mobile patterning units (Griveau et al., 2010). Further, as molecularly distinct CR subtypes anchor to RGs in specific cortical regions, this raises the possibility that CR subtypes enable the transmission of early cortical specifications in the cortical VZ to influence the patterning of cortical fields and the boundaries between functional areas in the postnatal cortex (Borello and Pierani, 2010; Griveau et al.,

23

2010; Arai and Pierani, 2014). Consistent with this, variations in CR subtypes migration speed and temporal invasion of cortical territories has recently been suggested to alter the sizes and boundaries between cortical areas (Barber et al., 2015). CRs in humans and nonhuman primates show more complex dendritic and axonal arborizations as well as more complex molecular profiles, when compared with either the mouse or chick, suggesting an increased morphological and molecular diversification of CRs during evolution (Marin-Padilla, 1998; Meyer and Goffinet, 1998; Meyer and Wahle, 1999; Yamazaki et al., 2004; Meyer et al., 2004; Cabrera-Socorro et al., 2007; Abellan et al., 2010a,b). Indeed, comparative studies show that the Reelin signal within CRs in the MZ has increased during evolution (Schiffmann et al., 1997; Meyer and Goffinet, 1998; Bernier et al., 2000; Tissir et al., 2002; Perez-Garcia et al., 2004) and it has been suggested that an amplification of Reelin signaling through the acquisition or expansion of CR progenitor domains, may have played a key role in the evolution of the cerebral cortex and in the establishment of cortical lamination (Bar and Goffinet, 2000; Tissir et al., 2002; Cabrera-Socorro et al., 2007; Meyer, 2010; Bielle et al. 2005). Consistent with this idea, is the expression in Reelin1 CRs of the human accelerated coding region 1 (HAR1), an RNA gene which belongs to ancestrally conserved genomic regions and shows a significantly accelerated rate of substitution in the human lineage (Pollard et al., 2006), suggesting human-specific traits and function of CRs. Moreover, given that CR subtypes are differentially enriched in morphogens and influence cortical patterning in the mouse (Griveau et al., 2010; Barber et al., 2015), this provides a potential mechanism by which the increased molecular diversification of CRs subtypes, as well as changes in their migratory properties, may have played a role in the expansion and diversification of functional cortical areas during evolution (Borello and Pierani, 2010; Arai and Pierani, 2014; Roy et al., 2014).

REFERENCE LIST Abe P, Mueller W, Schutz D, MacKay F, Thelen M, Zhang P, Stumm R. 2014. CXCR7 prevents excessive CXCL12mediated downregulation of CXCR4 in migrating cortical interneurons. Development 141:1857–1863. Abellan A, Menuet A, Dehay C, Medina L, Retaux S. 2010a. Differential expression of LIM-homeodomain factors in Cajal-Retzius cells of primates, rodents, and birds. Cereb Cortex 20:1788–1798. Abellan A, Vernier B, Retaux S, Medina L. 2010b. Similarities and differences in the forebrain expression of Lhx1 Developmental Neurobiology

24

Barber and Pierani

and Lhx5 between chicken and mouse: Insights for understanding telencephalic development and evolution. J Comp Neurol 518:3512–3528. Abercrombie M, Ambrose EJ. 1958. Interference microscope studies of cell contacts in tissue culture. Exp Cell Res 15:332–345. Abercrombie M, Heaysman JE. 1953. Observations on the social behaviour of cells in tissue culture. I. Speed of movement of chick heart fibroblasts in relation to their mutual contacts. Exp Cell Res 5:111–131. Abercrombie M, Heaysman JE. 1954. Observations on the social behaviour of cells in tissue culture. II. Monolayering of fibroblasts. Exp Cell Res 6:293–306. Abraham H, Meyer G. 2003. Reelin-expressing neurons in the postnatal and adult human hippocampal formation. Hippocampus 13:715–727. Aghajanian H, Choi C, Ho VC, Gupta M, Singh MK, Epstein JA. 2014. Semaphorin 3d and semaphorin 3e direct endothelial motility through distinct molecular signaling pathways. J Biol Chem 289:17971–17979. Aguilo A, Schwartz TH, Kumar VS, Peterlin ZA, Tsiola A, Soriano E, Yuste R. 1999. Involvement of cajal-retzius neurons in spontaneous correlated activity of embryonic and postnatal layer 1 from wild-type and reeler mice. J Neurosci 19:10856–10868. Albrieux M, Platel JC, Dupuis A, Villaz M, Moody WJ. 2004. Early expression of sodium channel transcripts and sodium current by cajal-retzius cells in the preplate of the embryonic mouse neocortex. J Neurosci 24:1719–1725. Alcantara S, Pozas E, Ibanez CF, Soriano E. 2006. BDNFmodulated spatial organization of Cajal-Retzius and GABAergic neurons in the marginal zone plays a role in the development of cortical organization. Cereb Cortex 16:487–499. Alcolado R, Weller RO, Parrish EP, Garrod D. 1988. The cranial arachnoid and pia mater in man: Anatomical and ultrastructural observations. Neuropathol Appl Neurobiol 14:1–17. Alifragis P, Liapi A, Parnavelas JG. 2004. Lhx6 regulates the migration of cortical interneurons from the ventral telencephalon but does not specify their GABA phenotype. J Neurosci 24:5643–5648. Allendoerfer KL, Shatz CJ. 1994. The subplate, a transient neocortical structure: its role in the development of connections between thalamus and cortex. Annu Rev Neurosci 17:185–218. Anderson SA, Eisenstat DD, Shi L, Rubenstein JL. 1997. Interneuron migration from basal forebrain to neocortex: Dependence on Dlx genes. Science 278:474–476. Anderson SA, Marin O, Horn C, Jennings K, Rubenstein JL. 2001. Distinct cortical migrations from the medial and lateral ganglionic eminences. Development 128:353–363. Andrews WD, Zito A, Memi F, Jones G, Tamamaki N, Parnavelas JG. 2013. Limk2 mediates semaphorin signalling in cortical interneurons migrating through the subpallium. Biol Open 2:277–282. Anstotz M, Cosgrove KE, Hack I, Mugnaini E, Maccaferri G, Lubke JH. 2014. Morphology, input-output relations Developmental Neurobiology

and synaptic connectivity of Cajal-Retzius cells in layer 1 of the developing neocortex of CXCR4-EGFP mice. Brain Struct Funct 219:2119–2139. Arai Y, Pierani A. 2014. Development and evolution of cortical fields. Neurosci Res 86:66–76. Arber S, Barbayannis FA, Hanser H, Schneider C, Stanyon CA, Bernard O, Caroni P. 1998. Regulation of actin dynamics through phosphorylation of cofilin by LIMkinase. Nature 393:805–809. Arikawa-Hirasawa E, Watanabe H, Takami H, Hassell JR, Yamada Y. 1999. Perlecan is essential for cartilage and cephalic development. Nat Genet 23:354–358. Bagri A, Gurney T, He X, Zou YR, Littman DR, TessierLavigne M, Pleasure SJ. 2002. The chemokine SDF1 regulates migration of dentate granule cells. Development 129:4249–4260. Bagri A, Tessier-Lavigne M. 2002. Neuropilins as Semaphorin receptors: In vivo functions in neuronal cell migration and axon guidance. Adv Exp Med Biol 515: 13–31. Baloyannis SJ. 2005. Morphological and morphometric alterations of Cajal-Retzius cells in early cases of Alzheimer’s disease: A Golgi and electron microscope study. Int J Neurosci 115:965–980. Bar I, Goffinet AM. 2000. Evolution of cortical lamination: the reelin/Dab1 pathway. Novartis Found Symp 228:114–125. Barber M, Arai Y, Morishita Y, Vigier L, Causeret F, Borello U, Ledonne F, et al. 2015. Migration speed of Cajal-Retzius cells modulated by vesicular trafficking controls the size of higher-order cortical areas. Curr Biol 25:2466–2478. Bauch H, Stier H, Schlosshauer B. 1998. Axonal versus dendritic outgrowth is differentially affected by radial glia in discrete layers of the retina. J Neurosci 18: 1774–1785. Bayer SA, Altman J. 1990. Development of layer I and the subplate in the rat neocortex. Exp Neurol 107:48–62. Belichenko PV, Vogt Weisenhorn DM, Myklossy J, Celio MR. 1995. Calretinin-positive Cajal-Retzius cells persist in the adult human neocortex. Neuroreport 6:1869–1874. Berger J, Berger S, Tuoc TC, D’Amelio M, Cecconi F, Gorski JA, Jones KR, et al. 2007a. Conditional activation of Pax6 in the developing cortex of transgenic mice causes progenitor apoptosis. Development 134: 1311–1322. Berger O, Li G, Han SM, Paredes M, Pleasure SJ. 2007b. Expression of SDF-1 and CXCR4 during reorganization of the postnatal dentate gyrus. Dev Neurosci 29:48–58. Bernier B, Bar I, D’Arcangelo G, Curran T, Goffinet AM. 2000. Reelin mRNA expression during embryonic brain development in the chick. J Comp Neurol 422:448–463. Bielle F, Griveau A, Narboux-Neme N, Vigneau S, Sigrist M, Arber S, Wassef M, et al. 2005. Multiple origins of Cajal-Retzius cells at the borders of the developing pallium. Nat Neurosci 8:1002–1012. Bishop KM, Garel S, Nakagawa Y, Rubenstein JL, O’Leary DD. 2003. Emx1 and Emx2 cooperate to

Tangential Migration of Glutamatergic Neurons regulate cortical size, lamination, neuronal differentiation, development of cortical efferents, and thalamocortical pathfinding. J Comp Neurol 457:345–360. Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. 1996. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1.SDF-1. J Exp Med 184:1101–1109. Boldajipour B, Mahabaleshwar H, Kardash E, ReichmanFried M, Blaser H, Minina S, Wilson D, et al. 2008. Control of chemokine-guided cell migration by ligand sequestration. Cell 132:463–473. Borello U, Pierani A. 2010. Patterning the cerebral cortex: Traveling with morphogens. Curr Opin Genet Dev 20: 408–415. Borrell V, Marin O. 2006. Meninges control tangential migration of hem-derived Cajal-Retzius cells via CXCL12/CXCR4 signaling. Nat Neurosci 9:1284–1293. Borrell V, Ruiz M, del Rio JA, Soriano E. 1999. Development of commissural connections in the hippocampus of reeler mice: Evidence of an inhibitory influence of CajalRetzius cells. Exp Neurol 156:268–282. Bribian A, Nocentini S, Llorens F, Gil V, Mire E, Reginensi D, Yoshida Y, Mann F, del Rio JA. 2014. Sema3E/PlexinD1 regulates the migration of hemderived Cajal-Retzius cells in developing cerebral cortex. Nat Commun 5:4265 Brunstrom JE, Gray-Swain MR, Osborne PA, Pearlman AL. 1997. Neuronal heterotopias in the developing cerebral cortex produced by neurotrophin-4. Neuron 18: 505–517. Bulchand S, Grove EA, Porter FD, Tole S. 2001. LIMhomeodomain gene Lhx2 regulates the formation of the cortical hem. Mech Dev 100:165–175. Bulchand S, Subramanian L, Tole S. 2003. Dynamic spatiotemporal expression of LIM genes and cofactors in the embryonic and postnatal cerebral cortex. Dev Dyn 226: 460–469. Bulfone A, Smiga SM, Shimamura K, Peterson A, Puelles L, Rubenstein JL. 1995. T-brain-1: A homolog of Brachyury whose expression defines molecularly distinct domains within the cerebral cortex. Neuron 15:63–78. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, et al. 2006. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med 203: 2201–2213. Bussolino F, Giraudo E, Serini G. 2014. Class 3 semaphorin in angiogenesis and lymphangiogenesis. Chem Immunol Allergy 99:71–88. Cabrera-Socorro A, Hernandez-Acosta NC, Gonzalez-Gomez M, Meyer G. 2007. Comparative aspects of p73 and Reelin expression in Cajal-Retzius cells and the cortical hem in lizard, mouse and human. Brain Res 1132:59–70. Camacho J, Ejaz E, Ariza J, Noctor SC, Martinez-Cerdeno V. 2014. RELN-expressing neuron density in layer I of the superior temporal lobe is similar in human brains with autism and in age-matched controls. Neurosci Lett 579: 163–167.

25

Carmona-Fontaine C, Matthews HK, Kuriyama S, Moreno M, Dunn GA, Parsons M, Stern CD, et al. 2008. Contact inhibition of locomotion in vivo controls neural crest directional migration. Nature 456:957–961. Caronia-Brown G, Grove EA. 2011. Timing of cortical interneuron migration is influenced by the cortical hem. Cereb Cortex 21:748–755. Casazza A, Finisguerra V, Capparuccia L, Camperi A, Swiercz JM, Rizzolio S, Rolny C, et al. 2010. Sema3EPlexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J Clin Invest 120: 2684–2698. Cecchi C, Boncinelli E. 2000. Emx homeogenes and mouse brain development. Trends Neurosci 23:347–352. Ceci ML, Lopez-Mascaraque L, De Carlos JA. 2010. The influence of the environment on Cajal-Retzius cell migration. Cereb Cortex 20:2348–2360. Ceci ML, Pedraza M, De Carlos JA. 2012. The embryonic septum and ventral pallium, new sources of olfactory cortex cells. PLoS One 7:e44716 Chai X, Fan L, Shao H, Lu X, Zhang W, Li J, Wang J, et al. 2015. Reelin Induces Branching of Neurons and Radial Glial Cells during Corticogenesis. Cereb Cortex 25:3640–3653. Epub 2014 Sep 21. Chapouton P, Gartner A, Gotz M. 1999. The role of Pax6 in restricting cell migration between developing cortex and basal ganglia. Development 126:5569–5579. Chauvet S, Cohen S, Yoshida Y, Fekrane L, Livet J, Gayet O, Segu L, et al. 2007. Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development. Neuron 56: 807–822. Chen H, He Z, Bagri A, Tessier-Lavigne M. 1998a. Semaphorin-neuropilin interactions underlying sympathetic axon responses to class III semaphorins. Neuron 21:1283–1290. Chen H, He Z, Tessier-Lavigne M. 1998b. Axon guidance mechanisms: Semaphorins as simultaneous repellents and anti-repellents. Nat Neurosci 1:436–439. Chen Y, Sharma RP, Costa RH, Costa E, Grayson DR. 2002. On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res 30:2930–2939. Chiara F, Badaloni A, Croci L, Yeh ML, Cariboni A, Hoerder-Suabedissen A, Consalez GG, et al. 2012. Early B-cell factors 2 and 3.EBF2/3. regulate early migration of Cajal-Retzius cells from the cortical hem. Dev Biol 365: 277–289. Chilcote TJ, Galli T, Mundigl O, Edelmann L, McPherson PS, Takei K, De CP. 1995. Cellubrevin and synaptobrevins: Similar subcellular localization and biochemical properties in PC12 cells. J Cell Biol 129:219–231. Choe Y, Huynh T, Pleasure SJ. 2014. Migration of oligodendrocyte progenitor cells is controlled by transforming growth factor beta family proteins during corticogenesis. J Neurosci 34:14973–14983. Choi YI, Duke-Cohan JS, Chen W, Liu B, Rossy J, Tabarin T, Ju L, et al. 2014. Dynamic control of beta1 integrin adhesion by the plexinD1-sema3E axis. Proc Natl Acad Sci USA 111:379–384. Developmental Neurobiology

26

Barber and Pierani

Chou SJ, Babot Z, Leingartner A, Studer M, Nakagawa Y, O’Leary DD. 2013. Geniculocortical input drives genetic distinctions between primary and higher-order visual areas. Science 340:1239–1242. Chowdhury TG, Jimenez JC, Bomar JM, Cruz-Martin A, Cantle JP, Portera-Cailliau C. 2010. Fate of cajal-retzius neurons in the postnatal mouse neocortex. Front Neuroanat 4:10 Chuang SM, Wang Y, Wang Q, Liu KM, Shen Q. 2011. Ebf2 marks early cortical neurogenesis and regulates the generation of cajal-retzius neurons in the developing cerebral cortex. Dev Neurosci 33:479–493. Chun JJ, Shatz CJ. 1989. Interstitial cells of the adult neocortical white matter are the remnant of the early generated subplate neuron population. J Comp Neurol 282: 555–569. Cobas A, Fairen A, Alvarez-Bolado G, Sanchez MP. 1991. Prenatal development of the intrinsic neurons of the rat neocortex: A comparative study of the distribution of GABA-immunoreactive cells and the GABAA receptor. Neuroscience 40:375–397. Cohen-Tannoudji M, Babinet C, Wassef M. 1994. Early determination of a mouse somatosensory cortex marker. Nature 368:460–463. Conover JC, Doetsch F, Garcia-Verdugo JM, Gale NW, Yancopoulos GD, Alvarez-Buylla A. 2000. Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone. Nat Neurosci 3:1091–1097. Corradi A, Croci L, Broccoli V, Zecchini S, Previtali S, Wurst W, Amadio S, et al. 2003. Hypogonadotropic hypogonadism and peripheral neuropathy in Ebf2-null mice. Development 130:401–410. Costell M, Gustafsson E, Aszodi A, Morgelin M, Bloch W, Hunziker E, Addicks K, et al. 1999. Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol 147:1109–1122. Cowan CA, Henkemeyer M. 2002. Ephrins in reverse, park and drive. Trends Cell Biol 12:339–346. Croci L, Chung SH, Masserdotti G, Gianola S, Bizzoca A, Gennarini G, Corradi A, et al. 2006. A key role for the HLH transcription factor EBF2COE2,O/E-3 in Purkinje neuron migration and cerebellar cortical topography. Development 133:2719–2729. Cubedo N, Cerdan E, Sapede D, Rossel M. 2009. CXCR4 and CXCR7 cooperate during tangential migration of facial motoneurons. Mol Cell Neurosci 40:474–484. D’Arcangelo G. 2006. Reelin mouse mutants as models of cortical development disorders. Epilepsy Behav 8:81–90. D’Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T. 1995. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374:719–723. D’Arcangelo G, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Curran T. 1997. Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. J Neurosci 17:23–31. Dambly-Chaudiere C, Cubedo N, Ghysen A. 2007. Control of cell migration in the development of the posterior latDevelopmental Neurobiology

eral line: Antagonistic interactions between the chemokine receptors CXCR4 and CXCR7/RDC1. BMC Dev Biol 7:23 Davis JR, Huang CY, Zanet J, Harrison S, Rosten E, Cox S, Soong DY, et al. 2012. Emergence of embryonic pattern through contact inhibition of locomotion. Development 139:4555–4560. De Carlos JA, Lopez-Mascaraque L, Valverde F. 1996. Dynamics of cell migration from the lateral ganglionic eminence in the rat. J Neurosci 16:6146–6156. De Carlos JA, O’Leary DD. 1992. Growth and targeting of subplate axons and establishment of major cortical pathways. J Neurosci 12:1194–1211. del Rio JA, Heimrich B, Borrell V, Forster E, Drakew A, Alcantara S, Nakajima K, et al. 1997. A role for CajalRetzius cells and reelin in the development of hippocampal connections. Nature 385:70–74. del Rio JA, Heimrich B, Super H, Borrell V, Frotscher M, Soriano E. 1996. Differential survival of Cajal-Retzius cells in organotypic cultures of hippocampus and neocortex. J Neurosci 16:6896–6907. del Rio JA, Martinez A, Fonseca M, Auladell C, Soriano E. 1995. Glutamate-like immunoreactivity and fate of CajalRetzius cells in the murine cortex as identified with calretinin antibody. Cereb Cortex 5:13–21. Demyanenko GP, Mohan V, Zhang X, Brennaman LH, Dharbal KE, Tran TS, Manis PB, et al. 2014. Neural cell adhesion molecule NrCAM regulates Semaphorin 3Finduced dendritic spine remodeling. J Neurosci 34: 11274–11287. Derer P, Derer M. 1990. Cajal-Retzius cell ontogenesis and death in mouse brain visualized with horseradish peroxidase and electron microscopy. Neuroscience 36: 839–856. Dixit R, Wilkinson G, Cancino GI, Shaker T, Adnani L, Li S, Dennis D, et al. 2014. Neurog1 and Neurog2 control two waves of neuronal differentiation in the piriform cortex. J Neurosci 34:539–553. Dixit R, Zimmer C, Waclaw RR, Mattar P, Shaker T, Kovach C, Logan C, et al. 2011. Ascl1 participates in Cajal-Retzius cell development in the neocortex. Cereb Cortex 21:2599–2611. Dona E, Barry JD, Valentin G, Quirin C, Khmelinskii A, Kunze A, Durdu S, et al. 2013. Directional tissue migration through a self-generated chemokine gradient. Nature 503:285–289. Dulabon L, Olson EC, Taglienti MG, Eisenhuth S, McGrath B, Walsh CA, Kreidberg JA, et al. 2000. Reelin binds alpha3beta1 integrin and inhibits neuronal migration. Neuron 27:33–44. Duveau V, Madhusudan A, Caleo M, Knuesel I, Fritschy JM. 2011. Impaired reelin processing and secretion by Cajal-Retzius cells contributes to granule cell dispersion in a mouse model of temporal lobe epilepsy. Hippocampus 21:935–944. Eastwood SL, Harrison PJ. 2006. Cellular basis of reduced cortical reelin expression in schizophrenia. Am J Psychiatry 163:540–542.

Tangential Migration of Glutamatergic Neurons Egea J, Klein R. 2007. Bidirectional Eph-ephrin signaling during axon guidance. Trends Cell Biol 17:230–238. Erzurumlu RS, Kind PC. 2001. Neural activity: Sculptor of ‘barrels’ in the neocortex. Trends Neurosci 24:589–595. Etchevers HC, Vincent C, Le Douarin NM, Couly GF. 2001. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development 128:1059–1068. Etienne-Manneville S, Hall A. 2002. Rho GTPases in cell biology. Nature 420:629–635. FALCONER DS.1951. Two new mutants, ‘trembler’ and ‘reeler’, with neurological actions in the house mouse.Mus musculus L. J Genet 50:192–201. Flames N, Long JE, Garratt AN, Fischer TM, Gassmann M, Birchmeier C, Lai C, et al. 2004. Short- and long-range attraction of cortical GABAergic interneurons by neuregulin-1. Neuron 44:251–261. Florio M, Huttner WB. 2014. Neural progenitors, neurogenesis and the evolution of the neocortex. Development 141:2182–2194. Forster E, Tielsch A, Saum B, Weiss KH, Johanssen C, Graus-Porta D, Muller U, et al. 2002. Reelin, Disabled 1, and beta 1 integrins are required for the formation of the radial glial scaffold in the hippocampus. Proc Natl Acad Sci USA 99:13178–13183. Franco SJ, Martinez-Garay I, Gil-Sanz C, Harkins-Perry SR, Muller U. 2011. Reelin regulates cadherin function via Dab1/Rap1 to control neuronal migration and lamination in the neocortex. Neuron 69:482–497. Friauf E, McConnell SK, Shatz CJ. 1990. Functional synaptic circuits in the subplate during fetal and early postnatal development of cat visual cortex. J Neurosci 10:2601– 2613. Friauf E, Shatz CJ. 1991. Changing patterns of synaptic input to subplate and cortical plate during development of visual cortex. J Neurophysiol 66:2059–2071. Fukumitsu H, Furukawa Y, Tsusaka M, Kinukawa H, Nitta A, Nomoto H, Mima T, et al. 1998. Simultaneous expression of brain-derived neurotrophic factor and neurotrophin-3 in Cajal-Retzius, subplate and ventricular progenitor cells during early development stages of the rat cerebral cortex. Neuroscience 84:115–127. Galli T, Chilcote T, Mundigl O, Binz T, Niemann H, De CP. 1994. Tetanus toxin-mediated cleavage of cellubrevin impairs exocytosis of transferrin receptor-containing vesicles in CHO cells. J Cell Biol 125:1015–1024. Ganju RK, Brubaker SA, Meyer J, Dutt P, Yang Y, Qin S, Newman W, et al. 1998. The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J Biol Chem 273: 23169–23175. Garcia-Dominguez M, Poquet C, Garel S, Charnay P. 2003. Ebf gene function is required for coupling neuronal differentiation and cell cycle exit. Development 130:6013–6025. Garcia-Moreno F, Lopez-Mascaraque L, De Carlos JA. 2007. Origins and migratory routes of murine CajalRetzius cells. J Comp Neurol 500:419–432.

27

Garel S, Garcia-Dominguez M, Charnay P. 2000. Control of the migratory pathway of facial branchiomotor neurones. Development 127:5297–5307. Garel S, Marin F, Grosschedl R, Charnay P. 1999. Ebf1 controls early cell differentiation in the embryonic striatum. Development 126:5285–5294. Garel S, Marin F, Mattei MG, Vesque C, Vincent A, Charnay P. 1997. Family of Ebf/Olf-1-related genes potentially involved in neuronal differentiation and regional specification in the central nervous system. Dev Dyn 210:191–205. Garel S, Yun K, Grosschedl R, Rubenstein JL. 2002. The early topography of thalamocortical projections is shifted in Ebf1 and Dlx1/2 mutant mice. Development 129: 5621–5634. Gay CM, Zygmunt T, Torres-Vazquez J. 2011. Diverse functions for the semaphorin receptor PlexinD1 in development and disease. Dev Biol 349:19. Ghosh A, Shatz CJ. 1993. A role for subplate neurons in the patterning of connections from thalamus to neocortex. Development 117:1031–1047. Gil-Sanz C, Franco SJ, Martinez-Garay I, Espinosa A, Harkins-Perry S, Muller U. 2013. Cajal-Retzius cells instruct neuronal migration by coincidence signaling between secreted and contact-dependent guidance cues. Neuron 79:461–477. Gitton Y, Cohen-Tannoudji M, Wassef M. 1999. Role of thalamic axons in the expression of H-2Z1, a mouse somatosensory cortex specific marker. Cereb Cortex 9: 611–620. Gorski JA, Talley T, Qiu M, Puelles L, Rubenstein JL, Jones KR. 2002. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1expressing lineage. J Neurosci 22:6309–6314. Gotz M, Stoykova A, Gruss P. 1998. Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21: 1031–1044. Graus-Porta D, Blaess S, Senften M, Littlewood-Evans A, Damsky C, Huang Z, Orban P, et al. 2001. Beta1-class integrins regulate the development of laminae and folia in the cerebral and cerebellar cortex. Neuron 31:367–379. Griveau A, Borello U, Causeret F, Tissir F, Boggetto N, Karaz S, Pierani A. 2010. A novel role for Dbx1-derived Cajal-Retzius cells in early regionalization of the cerebral cortical neuroepithelium. PLoS Biol 8:e1000440 Gu C, Giraudo E. 2013. The role of semaphorins and their receptors in vascular development and cancer. Exp Cell Res 319:1306–1316. Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J, Henderson CE, et al. 2005. Semaphorin 3E and plexinD1 control vascular pattern independently of neuropilins. Science 307:265–268. Gu X, Liu B, Wu X, Yan Y, Zhang Y, Wei Y, Pleasure SJ, et al. 2011. Inducible genetic lineage tracing of cortical hem derived Cajal-Retzius cells reveals novel properties. PLoS One 6:e28653 Gulisano M, Broccoli V, Pardini C, Boncinelli E. 1996. Emx1 and Emx2 show different patterns of expression Developmental Neurobiology

28

Barber and Pierani

during proliferation and differentiation of the developing cerebral cortex in the mouse. Eur J Neurosci 8:1037–1050. Halfter W, Dong S, Yip YP, Willem M, Mayer U. 2002. A critical function of the pial basement membrane in cortical histogenesis. J Neurosci 22:6029–6040. Hanashima C, Fernandes M, Hebert JM, Fishell G. 2007. The role of Foxg1 and dorsal midline signaling in the generation of Cajal-Retzius subtypes. J Neurosci 27: 11103–11111. Hartfuss E, Forster E, Bock HH, Hack MA, Leprince P, Luque JM, Herz J, et al. 2003. Reelin signaling directly affects radial glia morphology and biochemical maturation. Development 130:4597–4609. Hartmann D, De SB, Saftig P. 1999. Presenilin-1 deficiency leads to loss of Cajal-Retzius neurons and cortical dysplasia similar to human type 2 lissencephaly. Curr Biol 9: 719–727. Hartwig C, Veske A, Krejcova S, Rosenberger G, Finckh U. 2005. Plexin B3 promotes neurite outgrowth, interacts homophilically, and interacts with Rin. BMC Neurosci 6:53 Hatanaka Y, Hisanaga S, Heizmann CW, Murakami F. 2004. Distinct migratory behavior of early- and late-born neurons derived from the cortical ventricular zone. J Comp Neurol 479:1–14. Hernandez-Miranda LR, Cariboni A, Faux C, Ruhrberg C, Cho JH, Cloutier JF, Eickholt BJ, et al. 2011. Robo1 regulates semaphorin signaling to guide the migration of cortical interneurons through the ventral forebrain. J Neurosci 31:6174–6187. Hevner RF, Daza RA, Englund C, Kohtz J, Fink A. 2004. Postnatal shifts of interneuron position in the neocortex of normal and reeler mice: Evidence for inward radial migration. Neuroscience 124:605–618. Hevner RF, Neogi T, Englund C, Daza RA, Fink A. 2003. Cajal-Retzius cells in the mouse: Transcription factors, neurotransmitters, and birthdays suggest a pallial origin. Brain Res Dev Brain Res 141:39–53. Hevner RF, Shi L, Justice N, Hsueh Y, Sheng M, Smiga S, Bulfone A, et al. 2001. Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29:353–366. Higashi S, Hioki K, Kurotani T, Kasim N, Molnar Z. 2005. Functional thalamocortical synapse reorganization from subplate to layer IV during postnatal development in the reeler-like mutant rat.shaking rat Kawasaki. J Neurosci 25:1395–1406. Higashi S, Molnar Z, Kurotani T, Toyama K. 2002. Prenatal development of neural excitation in rat thalamocortical projections studied by optical recording. Neuroscience 115:1231–1246. Hoerder-Suabedissen A, Molnar Z. 2012. Morphology of mouse subplate cells with identified projection targets changes with age. J Comp Neurol 520:174–185. Hoerder-Suabedissen A, Molnar Z. 2013. Molecular diversity of early-born subplate neurons. Cereb Cortex 23: 1473–1483. Hoerder-Suabedissen A, Molnar Z. 2015. Development, evolution and pathology of neocortical subplate neurons. Nat Rev Neurosci 16:133–146. Developmental Neurobiology

Hoerder-Suabedissen A, Oeschger FM, Krishnan ML, Belgard TG, Wang WZ, Lee S, Webber C, et al. 2013. Expression profiling of mouse subplate reveals a dynamic gene network and disease association with autism and schizophrenia. Proc Natl Acad Sci USA 110:3555–3560. Hoerder-Suabedissen A, Wang WZ, Lee S, Davies KE, Goffinet AM, Rakic S, Parnavelas J, et al. 2009. Novel markers reveal subpopulations of subplate neurons in the murine cerebral cortex. Cereb Cortex 19:1738–1750. Hoffmann F, Muller W, Schutz D, Penfold ME, Wong YH, Schulz S, Stumm R. 2012. Rapid uptake and degradation of CXCL12 depend on CXCR7 carboxyl-terminal serine/ threonine residues. J Biol Chem 287:28362–28377. Holmberg J, Armulik A, Senti KA, Edoff K, Spalding K, Momma S, Cassidy R, et al. 2005. Ephrin-A2 reverse signaling negatively regulates neural progenitor proliferation and neurogenesis. Genes Dev 19:462–471. Imayoshi I, Shimogori T, Ohtsuka T, Kageyama R. 2008. Hes genes and neurogenin regulate non-neural versus neural fate specification in the dorsal telencephalic midline. Development 135:2531–2541. Inoue T, Ogawa M, Mikoshiba K, Aruga J. 2008. Zic deficiency in the cortical marginal zone and meninges results in cortical lamination defects resembling those in type II lissencephaly. J Neurosci 28:4712–4725. Inoue T, Ota M, Ogawa M, Mikoshiba K, Aruga J. 2007. Zic1 and Zic3 regulate medial forebrain development through expansion of neuronal progenitors. J Neurosci 27:5461–5473. Janssen BJ, Malinauskas T, Weir GA, Cader MZ, Siebold C, Jones EY. 2012. Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex. Nat Struct Mol Biol 19:1293–1299. Jiao JW, Feldheim DA, Chen DF. 2008. Ephrins as negative regulators of adult neurogenesis in diverse regions of the central nervous system. Proc Natl Acad Sci USA 105: 8778–8783. Jimenez D, Rivera R, Lopez-Mascaraque L, De Carlos JA. 2003. Origin of the cortical layer I in rodents. Dev Neurosci 25:105–115. Judas M, Sedmak G, Kostovic I. 2013. The significance of the subplate for evolution and developmental plasticity of the human brain. Front Hum Neurosci 7:423 Kanold PO, Kara P, Reid RC, Shatz CJ. 2003. Role of subplate neurons in functional maturation of visual cortical columns. Science 301:521–525. Kerjan G, Dolan J, Haumaitre C, Schneider-Maunoury S, Fujisawa H, Mitchell KJ, Chedotal A. 2005. The transmembrane semaphorin Sema6A controls cerebellar granule cell migration. Nat Neurosci 8:1516–1524. Khodosevich K, Watanabe Y, Monyer H. 2011. EphA4 preserves postnatal and adult neural stem cells in an undifferentiated state in vivo. J Cell Sci 124:1268–1279. Klein R. 2012. Eph/ephrin signalling during development. Development 139:4105–4109. Klein RS, Rubin JB, Gibson HD, DeHaan EN, AlvarezHernandez X, Segal RA, Luster AD. 2001. SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-

Tangential Migration of Glutamatergic Neurons induced proliferation of cerebellar granule cells. Development 128:1971–1981. Konig N, Valat J, Fulcrand J, Marty R. 1977. The time of origin of Cajal-Retzius cells in the rat temporal cortex. An autoradiographic study. Neurosci Lett 4:21–26. Kostovic I, Rakic P. 1990. Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain. J Comp Neurol 297:441–470. Krisch B, Leonhardt H, Oksche A. 1983. The meningeal compartments of the median eminence and the cortex. A comparative analysis in the rat. Cell Tissue Res 228:597–640. Krisch B, Leonhardt H, Oksche A. 1984. Compartments and perivascular arrangement of the meninges covering the cerebral cortex of the rat. Cell Tissue Res 238:459–474. Kruger RP, Aurandt J, Guan KL. 2005. Semaphorins command cells to move. Nat Rev Mol Cell Biol 6:789–800. Kupferman JV, Basu J, Russo MJ, Guevarra J, Cheung SK, Siegelbaum SA. 2014. Reelin signaling specifies the molecular identity of the pyramidal neuron distal dendritic compartment. Cell 158:1335–1347. Kusakawa Y, Mikawa S, Sato K. 2015. BMP5 expression in the adult rat brain. Neuroscience 284:972–987. Kwon HJ, Ma S, Huang Z. 2011. Radial glia regulate Cajal-Retzius cell positioning in the early embryonic cerebral cortex. Dev Biol 351:25–34. Lakoma J, Garcia-Alonso L, Luque JM. 2011. Reelin sets the pace of neocortical neurogenesis. Development 138: 5223–5234. Lavdas AA, Grigoriou M, Pachnis V, Parnavelas JG. 1999. The medial ganglionic eminence gives rise to a population of early neurons in the developing cerebral cortex. J Neurosci 19:7881–7888. Le Douarin NM, Brito JM, Creuzet S. 2007. Role of the neural crest in face and brain development. Brain Res Rev 55:237–247. Lee JA, Cole GJ. 2000. Localization of transitin mRNA, a nestin-like intermediate filament family member, in chicken radial glia processes. J Comp Neurol 418:473–483. Li G, Adesnik H, Li J, Long J, Nicoll RA, Rubenstein JL, Pleasure SJ. 2008a. Regional distribution of cortical interneurons and development of inhibitory tone are regulated by Cxcl12/Cxcr4 signaling. J Neurosci 28: 1085–1098. Li S, Jin Z, Koirala S, Bu L, Xu L, Hynes RO, Walsh CA, et al. 2008b. GPR56 regulates pial basement membrane integrity and cortical lamination. J Neurosci 28:5817–5826. Li YN, Radner S, French MM, Pinzon-Duarte G, Daly GH, Burgeson RE, Koch M, et al. 2012. The gamma3 chain of laminin is widely but differentially expressed in murine basement membranes: Expression and functional studies. Matrix Biol 31:120–134. Libby RT, Champliaud MF, Claudepierre T, Xu Y, Gibbons EP, Koch M, Burgeson RE, et al. 2000. Laminin expression in adult and developing retinae: evidence of two novel CNS laminins. J Neurosci 20:6517–6528. Lopes CA, Mair WG. 1974. Ultrastructure of the outer cortex and the pia mater in man. Acta Neuropathol 28:79–86.

29

Lopez-Bendito G, Molnar Z. 2003. Thalamocortical development: how are we going to get there? Nat Rev Neurosci 4:276–289. Lopez-Bendito G, Sanchez-Alcaniz JA, Pla R, Borrell V, Pico E, Valdeolmillos M, Marin O. 2008. Chemokine signaling controls intracortical migration and final distribution of GABAergic interneurons. J Neurosci 28:1613–1624. Lu Q, Sun EE, Klein RS, Flanagan JG. 2001. Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell 105:69–79. Luhmann HJ, Kilb W, Hanganu-Opatz IL. 2009. Subplate cells: amplifiers of neuronal activity in the developing cerebral cortex. Front Neuroanat 3:19 Luker KE, Steele JM, Mihalko LA, Ray P, Luker GD. 2010. Constitutive and chemokine-dependent internalization and recycling of CXCR7 in breast cancer cells to degrade chemokine ligands. Oncogene 29:4599–4610. Luo R, Jeong SJ, Jin Z, Strokes N, Li S, Piao X. 2011. G protein-coupled receptor 56 and collagen III, a receptorligand pair, regulates cortical development and lamination. Proc Natl Acad Sci USA 108:12925–12930. Luo Y, Raible D, Raper JA. 1993. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75:217–227. Luque JM. 2004. Integrin and the Reelin-Dab1 pathway: A sticky affair? Brain Res Dev Brain Res 152:269–271. Luque JM, Morante-Oria J, Fairen A. 2003. Localization of ApoER2, VLDLR and Dab1 in radial glia: Groundwork for a new model of reelin action during cortical development. Brain Res Dev Brain Res 140:195–203. Luskin MB, Shatz CJ. 1985. Studies of the earliest generated cells of the cat’s visual cortex: Cogeneration of subplate and marginal zones. J Neurosci 5:1062–1075. Lysko DE, Putt M, Golden JA. 2011. SDF1 regulates leading process branching and speed of migrating interneurons. J Neurosci 31:1739–1745. Lysko DE, Putt M, Golden JA. 2014. SDF1 reduces interneuron leading process branching through dual regulation of actin and microtubules. J Neurosci 34:4941–4962. Ma J, Yao XH, Fu Y, Yu YC. 2014. Development of layer 1 neurons in the mouse neocortex. Cereb Cortex 24: 2604–2618. Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, et al. 1998. Impaired Blymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in C. Proc Natl Acad Sci USA 95: 9448–9453. Magdaleno S, Keshvara L, Curran T. 2002. Rescue of ataxia and preplate splitting by ectopic expression of Reelin in reeler mice. Neuron 33:573–586. Maisonpierre PC, Belluscio L, Friedman B, Alderson RF, Wiegand SJ, Furth ME, Lindsay RM, et al. 1990. NT-3, BDNF, and NGF in the developing rat nervous system: Parallel as well as reciprocal patterns of expression. Neuron 5:501–509. Mallamaci A, Mercurio S, Muzio L, Cecchi C, Pardini CL, Gruss P, Boncinelli E. 2000a. The lack of Emx2 causes Developmental Neurobiology

30

Barber and Pierani

impairment of Reelin signaling and defects of neuronal migration in the developing cerebral cortex. J Neurosci 20:1109–1118. Mallamaci A, Muzio L, Chan CH, Parnavelas J, Boncinelli E. 2000b. Area identity shifts in the early cerebral cortex of Emx2-/- mutant mice. Nat Neurosci 3:679–686. Mallamaci A, Stoykova A. 2006. Gene networks controlling early cerebral cortex arealization. Eur J Neurosci 23: 847–856. Marin O, Yaron A, Bagri A, Tessier-Lavigne M, Rubenstein JL. 2001. Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Science 293:872–875. Marin-Padilla M. 1983. Structural organization of the human cerebral cortex prior to the appearance of the cortical plate. Anat Embryol Berl 168:21–40. Marin-Padilla M. 1990. Three-dimensional structural organization of layer I of the human cerebral cortex: A Golgi study. J Comp Neurol 299:89–105. Marin-Padilla M. 1998. Cajal-Retzius cells and the development of the neocortex. Trends Neurosci 21:64–71. Marin-Padilla M, Marin-Padilla TM. 1982. Origin, prenatal development and structural organization of layer I of the human cerebral.motor. cortex. A Golgi study. Anat Embryol Berl 164:161–206. Martin R, Gutierrez A, Penafiel A, Marin-Padilla M, de la Calle A. 1999. Persistence of Cajal-Retzius cells in the adult human cerebral cortex. An immunohistochemical study. Histol Histopathol 14:487–490. Martinez-Galan JR, Moncho-Bogani J, Caminos E. 2014. Expression of calcium-binding proteins in layer 1 reelinimmunoreactive cells during rat and mouse neocortical development. J Histochem Cytochem 62:60–69. Martinez-Garcia F, Gonzalez-Hernandez T, Martinez-Millan L. 1994. Pyramidal and nonpyramidal callosal cells in the striate cortex of the adult rat. J Comp Neurol 350:439–451. McConnell SK, Ghosh A, Shatz CJ. 1989. Subplate neurons pioneer the first axon pathway from the cerebral cortex. Science 245:978–982. McConnell SK, Ghosh A, Shatz CJ. 1994. Subplate pioneers and the formation of descending connections from cerebral cortex. J Neurosci 14:1892–1907. Medina L, Legaz I, Gonzalez G, De CF, Rubenstein JL, Puelles L. 2004. Expression of Dbx1, Neurogenin 2, Semaphorin 5A, Cadherin 8, and Emx1 distinguish ventral and lateral pallial histogenetic divisions in the developing mouse claustroamygdaloid complex. J Comp Neurol 474:504–523. Memi F, Abe P, Cariboni A, MacKay F, Parnavelas JG, Stumm R. 2013. CXC chemokine receptor 7.CXCR7. affects the migration of GnRH neurons by regulating CXCL12 availability. J Neurosci 33:17527–17537. Mendes-da-Cruz DA, et al. 2014. Semaphorin 3F and neuropilin-2 control the migration of human T-cell precursors. PLoS One 9:e103405. Meng X, Kao JP, Kanold PO. 2014. Differential signaling to subplate neurons by spatially specific silent synapses in developing auditory cortex. J Neurosci 34:8855–8864. Developmental Neurobiology

Meyer G. 2010. Building a human cortex: The evolutionary differentiation of Cajal-Retzius cells and the cortical hem. J Anat 217:334–343. Meyer G, Cabrera SA, Perez Garcia CG, Martinez ML, Walker N, Caput D. 2004. Developmental roles of p73 in Cajal-Retzius cells and cortical patterning. J Neurosci 24: 9878–9887. Meyer G, Goffinet AM. 1998. Prenatal development of reelin-immunoreactive neurons in the human neocortex. J Comp Neurol 397:29–40. Meyer G, Perez-Garcia CG, Abraham H, Caput D. 2002. Expression of p73 and Reelin in the developing human cortex. J Neurosci 22:4973–4986. Meyer G, Schaaps JP, Moreau L, Goffinet AM. 2000. Embryonic and early fetal development of the human neocortex. J Neurosci 20:1858–1868. Meyer G, Soria JM, Martinez-Galan JR, Martin-Clemente B, Fairen A. 1998. Different origins and developmental histories of transient neurons in the marginal zone of the fetal and neonatal rat cortex. J Comp Neurol 397: 493–518. Meyer G, Wahle P. 1999. The paleocortical ventricle is the origin of reelin-expressing neurons in the marginal zone of the foetal human neocortex. Eur J Neurosci 11: 3937–3944. Miquelajauregui A, Varela-Echavarria A, Ceci ML, Garcia-Moreno F, Ricano I, Hoang K, Frade-Perez D, et al. 2010. LIM-homeobox gene Lhx5 is required for normal development of Cajal-Retzius cells. J Neurosci 30:10551–10562. Miyashita-Lin EM, Hevner R, Wassarman KM, Martinez S, Rubenstein JL. 1999. Early neocortical regionalization in the absence of thalamic innervation. Science 285:906–909. Miyata T, Kawaguchi A, Okano H, Ogawa M. 2001. Asymmetric inheritance of radial glial fibers by cortical neurons. Neuron 31:727–741. Montiel JF, Wang WZ, Oeschger FM, HoerderSuabedissen A, Tung WL, Garcia-Moreno F, Holm IE, et al. 2011. Hypothesis on the dual origin of the Mammalian subplate. Front Neuroanat 5:25 Moore SA, Saito F, Chen J, Michele DE, Henry MD, Messing A, Cohn RD, et al. 2002. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 418:422–425. Movassagh H, Shan L, Halayko AJ, Roth M, Tamm M, Chakir J, Gounni AS. 2014. Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration. J Allergy Clin Immunol 133:560–567. Muzio L, Mallamaci A. 2003. Emx1, emx2 and pax6 in specification, regionalization and arealization of the cerebral cortex. Cereb Cortex 13:641–647. Myshrall TD, Moore SA, Ostendorf AP, Satz JS, Kowalczyk T, Nguyen H, Daza RA, et al. 2012. Dystroglycan on radial glia end feet is required for pial basement membrane integrity and columnar organization of the developing cerebral cortex. J Neuropathol Exp Neurol 71:1047–1063.

Tangential Migration of Glutamatergic Neurons Nadarajah B, Alifragis P, Wong RO, Parnavelas JG. 2003. Neuronal migration in the developing cerebral cortex: Observations based on real-time imaging. Cereb Cortex 13:607–611. Nadarajah B, Brunstrom JE, Grutzendler J, Wong RO, Pearlman AL. 2001. Two modes of radial migration in early development of the cerebral cortex. Nat Neurosci 4: 143–150. Nagai T, Aruga J, Minowa O, Sugimoto T, Ohno Y, Noda T, Mikoshiba K. 2000. Zic2 regulates the kinetics of neurulation. Proc Natl Acad Sci USA 97:1618–1623. Nagai T, Aruga J, Takada S, Gunther T, Sporle R, Schughart K, Mikoshiba K. 1997. The expression of the mouse Zic1, Zic2, and Zic3 gene suggests an essential role for Zic genes in body pattern formation. Dev Biol 182:299–313. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, Yoshida N, et al. 1996. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/ SDF-1. Nature 382:635–638. Naumann U, Cameroni E, Pruenster M, Mahabaleshwar H, Raz E, Zerwes HG, Rot A, et al. 2010. CXCR7 functions as a scavenger for CXCL12 and CXCL11. PLoS One 5: e9175 Negishi M, Katoh H. 2002. Rho family GTPases as key regulators for neuronal network formation. J Biochem 132:157–166. Nery S, Fishell G, Corbin JG. 2002. The caudal ganglionic eminence is a source of distinct cortical and subcortical cell populations. Nat Neurosci 5:1279–1287. Niclou SP, Franssen EH, Ehlert EM, Taniguchi M, Verhaagen J. 2003. Meningeal cell-derived semaphorin 3A inhibits neurite outgrowth. Mol Cell Neurosci 24: 902–912. Noctor SC, Martinez-Cerdeno V, Ivic L, Kriegstein AR. 2004. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci 7:136–144. North HA, Zhao X, Kolk SM, Clifford MA, Ziskind DM, Donoghue MJ. 2009. Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling. Development 136:2467–2476. O’Leary DD. 1989. Do cortical areas emerge from a protocortex? Trends Neurosci 12:400–406. O’Rourke NA, Dailey ME, Smith SJ, McConnell SK. 1992. Diverse migratory pathways in the developing cerebral cortex. Science 258:299–302. Ogawa M, Miyata T, Nakajima K, Yagyu K, Seike M, Ikenaka K, Yamamoto H, et al. 1995. The reeler geneassociated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron 14:899–912. Oh WJ, Gu C. 2013. The role and mechanism-of-action of Sema3E and Plexin-D1 in vascular and neural development. Semin Cell Dev Biol 24:156–162. Paredes MF, Li G, Berger O, Baraban SC, Pleasure SJ. 2006. Stromal-derived factor-1.CXCL12. regulates lami-

31

nar position of Cajal-Retzius cells in normal and dysplastic brains. J Neurosci 26:9404–9412. Parnavelas JG, Edmunds SM. 1983. Further evidence that Retzius-Cajal cells transform to nonpyramidal neurons in the developing rat visual cortex. J Neurocytol 12:863–871. Pedraza M, Hoerder-Suabedissen A, Albert-Maestro MA, Molnar Z, De Carlos JA. 2014. Extracortical origin of some murine subplate cell populations. Proc Natl Acad Sci USA 111:8613–8618. Perez-Garcia CG, Tissir F, Goffinet AM, Meyer G. 2004. Reelin receptors in developing laminated brain structures of mouse and human. Eur J Neurosci 20:2827–2832. Pinon MC, Jethwa A, Jacobs E, Campagnoni A, Molnar Z. 2009. Dynamic integration of subplate neurons into the cortical barrel field circuitry during postnatal development in the Golli-tau-eGFP.GTE. mouse. J Physiol 587: 1903–1915. Pla R, Borrell V, Flames N, Marin O. 2006. Layer acquisition by cortical GABAergic interneurons is independent of Reelin signaling. J Neurosci 26:6924–6934. Pollard KS, Salama SR, Lambert N, Lambot MA, Coppens S, Pedersen JS, Katzman S, et al. 2006. An RNA gene expressed during cortical development evolved rapidly in humans. Nature 443:167–172. Price DJ, Aslam S, Tasker L, Gillies K. 1997. Fates of the earliest generated cells in the developing murine neocortex. J Comp Neurol 377:414–422. Proux-Gillardeaux V, Gavard J, Irinopoulou T, Mege RM, Galli T. 2005a. Tetanus neurotoxin-mediated cleavage of cellubrevin impairs epithelial cell migration and integrindependent cell adhesion. Proc Natl Acad Sci USA 102: 6362–6367. Proux-Gillardeaux V, Rudge R, Galli T. 2005b. The tetanus neurotoxin-sensitive and insensitive routes to and from the plasma membrane: fast and slow pathways? Traffic 6: 366–373. Qiu R, Wang X, Davy A, Wu C, Murai K, Zhang H, Flanagan JG, et al. 2008. Regulation of neural progenitor cell state by ephrin-B. J Cell Biol 181:973–983. Quattrocolo G, Maccaferri G. 2014. Optogenetic activation of cajal-retzius cells reveals their glutamatergic output and a novel feedforward circuit in the developing mouse hippocampus. J Neurosci 34:13018–13032. Quinn JC, Molinek M, Martynoga BS, Zaki PA, Faedo A, Bulfone A, Hevner RF, et al. 2007. Pax6 controls cerebral cortical cell number by regulating exit from the cell cycle and specifies cortical cell identity by a cell autonomous mechanism. Dev Biol 302:50–65. Radner S, Banos C, Bachay G, Li YN, Hunter DD, Brunken WJ, Yee KT. 2013. beta2 and gamma3 laminins are critical cortical basement membrane components: Ablation of Lamb2 and Lamc3 genes disrupts cortical lamination and produces dysplasia. Dev Neurobiol 73: 209–229. Radnikow G, Feldmeyer D, Lubke J. 2002. Axonal projection, input and output synapses, and synaptic physiology of Cajal-Retzius cells in the developing rat neocortex. J Neurosci 22:6908–6919. Developmental Neurobiology

32

Barber and Pierani

Raedler E, Raedler A. 1978. Autoradiographic study of early neurogenesis in rat neocortex. Anat Embryol Berl 154:267–284. Rakic P. 1978. Neuronal migration and contact guidance in the primate telencephalon. Postgrad Med J 54(Suppl 1): 25–40. Rakic S, Zecevic N. 2003. Emerging complexity of layer I in human cerebral cortex. Cereb Cortex 13:1072–1083. Ramsey HJ. 1965. Fine structure of the surface of the cerebral cortex of human brain. J Cell Biol 26:323–334. Reep RL. 2000. Cortical layer VII and persistent subplate cells in mammalian brains. Brain Behav Evol 56:212– 234. Retaux S, Rogard M, Bach I, Failli V, Besson MJ. 1999. Lhx9: A novel LIM-homeodomain gene expressed in the developing forebrain. J Neurosci 19:783–793. Riedel A, Miettinen R, Stieler J, Mikkonen M, Alafuzoff I, Soininen H, Arendt T. 2003. Reelin-immunoreactive Cajal-Retzius cells: The entorhinal cortex in normal aging and Alzheimer’s disease. Acta Neuropathol 106: 291–302. Riggs KA, Hasan N, Humphrey D, Raleigh C, Nevitt C, Corbin D, Hu C. 2012. Regulation of integrin endocytic recycling and chemotactic cell migration by syntaxin 6 and VAMP3 interaction. J Cell Sci 125:3827–3839. Ringstedt T, Linnarsson S, Wagner J, Lendahl U, Kokaia Z, Arenas E, Ernfors P, et al. 1998. BDNF regulates reelin expression and Cajal-Retzius cell development in the cerebral cortex. Neuron 21:305–315. Roy A, Gonzalez-Gomez M, Pierani A, Meyer G, Tole S. 2014. Lhx2 regulates the development of the forebrain hem system. Cereb Cortex 24:1361–1372. Ryu CH, Park SA, Kim SM, Lim JY, Jeong CH, Jun JA, Oh JH, et al. 2010. Migration of human umbilical cord blood mesenchymal stem cells mediated by stromal cellderived factor-1/CXCR4 axis via Akt, ERK, and p38 signal transduction pathways. Biochem Biophys Res Commun 398:105–110. Salvucci O, de la Luz SM, Martina JA, McCormick PJ, Tosato G. 2006. EphB2 and EphB4 receptors forward signaling promotes SDF-1-induced endothelial cell chemotaxis and branching remodeling. Blood 108:2914–2922. Sanchez-Alcaniz JA, Haege S, Mueller W, Pla R, MacKay F, Schulz S, Lopez-Bendito G, et al. 2011. Cxcr7 controls neuronal migration by regulating chemokine responsiveness. Neuron 69:77–90. Saulnier A, Keruzore M, De CS, Bar I, Moers V, Magnani D, Walcher T, et al. 2013. The doublesex homolog Dmrt5 is required for the development of the caudomedial cerebral cortex in mammals. Cereb Cortex 23:2552–2567. Schiffmann SN, Bernier B, Goffinet AM. 1997. Reelin mRNA expression during mouse brain development. Eur J Neurosci 9:1055–1071. Schwarting GA, Henion TR, Nugent JD, Caplan B, Tobet S. 2006. Stromal cell-derived factor-1.chemokine C-X-C motif ligand 12. and chemokine C-X-C motif receptor 4 are required for migration of gonadotropin-releasing hormone neurons to the forebrain. J Neurosci 26:6834–6840. Developmental Neurobiology

Segklia A, Seuntjens E, Elkouris M, Tsalavos S, Stappers E, Mitsiadis TA, Huylebroeck D, et al. 2012. Bmp7 regulates the survival, proliferation, and neurogenic properties of neural progenitor cells during corticogenesis in the mouse. PLoS One 7:e34088 Sekine K, Honda T, Kawauchi T, Kubo K, Nakajima K. 2011. The outermost region of the developing cortical plate is crucial for both the switch of the radial migration mode and the Dab1-dependent “inside-out” lamination in the neocortex. J Neurosci 31:9426–9439. Sekine K, Kubo K, Nakajima K. 2014. How does Reelin control neuronal migration and layer formation in the developing mammalian neocortex? Neurosci Res 86:50–58. Shatz CJ, Luskin MB. 1986. The relationship between the geniculocortical afferents and their cortical target cells during development of the cat’s primary visual cortex. J Neurosci 6:3655–3668. Shearer MC, Niclou SP, Brown D, Asher RA, Holtmaat AJ, Levine JM, Verhaagen J, et al. 2003. The astrocyte/ meningeal cell interface is a barrier to neurite outgrowth which can be overcome by manipulation of inhibitory molecules or axonal signalling pathways. Mol Cell Neurosci 24:913–925. Shibata M, Kurokawa D, Nakao H, Ohmura T, Aizawa S. 2008. MicroRNA-9 modulates Cajal-Retzius cell differentiation by suppressing Foxg1 expression in mouse medial pallium. J Neurosci 28:10415–10421. Shimamura K, Rubenstein JL. 1997. Inductive interactions direct early regionalization of the mouse forebrain. Development 124:2709–2718. Shimogori T, Grove EA. 2005. Fibroblast growth factor 8 regulates neocortical guidance of area-specific thalamic innervation. J Neurosci 25:6550–6560. Shinozaki K, Miyagi T, Yoshida M, Miyata T, Ogawa M, Aizawa S, Suda Y. 2002. Absence of Cajal-Retzius cells and subplate neurons associated with defects of tangential cell migration from ganglionic eminence in Emx1/2 double mutant cerebral cortex. Development 129:3479–3492. Shirozu M, Nakano T, Inazawa J, Tashiro K, Tada H, Shinohara T, Honjo T. 1995. Structure and chromosomal localization of the human stromal cell-derived factor 1.SDF1. gene. Genomics 28:495–500. Siegenthaler JA, Ashique AM, Zarbalis K, Patterson KP, Hecht JH, Kane MA, Folias AE, et al. 2009. Retinoic acid from the meninges regulates cortical neuron generation. Cell 139:597–609. Sierro F, Biben C, Martinez-Munoz L, Mellado M, Ransohoff RM, Li M, Woehl B, et al. 2007. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci USA 104:14759–14764. Sievers J, Pehlemann FW, Gude S, Berry M. 1994. Meningeal cells organize the superficial glia limitans of the cerebellum and produce components of both the interstitial matrix and the basement membrane. J Neurocytol 23: 135–149. Simeone A, Gulisano M, Acampora D, Stornaiuolo A, Rambaldi M, Boncinelli E. 1992. Two vertebrate

Tangential Migration of Glutamatergic Neurons homeobox genes related to the Drosophila empty spiracles gene are expressed in the embryonic cerebral cortex. Embo J 11:2541–2550. Singer K, Luo R, Jeong SJ, Piao X. 2013. GPR56 and the developing cerebral cortex: Cells, matrix, and neuronal migration. Mol Neurobiol 47:186–196. Skalski M, Yi Q, Kean MJ, Myers DW, Williams KC, Burtnik A, Coppolino MG. 2010. Lamellipodium extension and membrane ruffling require different SNAREmediated trafficking pathways. BMC Cell Biol 11:62 Slezak M, et al. 2012. Relevance of exocytotic glutamate release from retinal glia. Neuron 74:504–516. Smart IH, Dehay C, Giroud P, Berland M, Kennedy H. 2002. Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey. Cereb Cortex 12:37–53. Smith D, Wagner E, Koul O, McCaffery P, Drager UC. 2001. Retinoic acid synthesis for the developing telencephalon. Cereb Cortex 11:894–905. Soriano E, Alvarado-Mallart RM, Dumesnil N, del Rio JA, Sotelo C. 1997. Cajal-Retzius cells regulate the radial glia phenotype in the adult and developing cerebellum and alter granule cell migration. Neuron 18:563–577. Stoykova A, Hatano O, Gruss P, Gotz M. 2003. Increase in reelin-positive cells in the marginal zone of Pax6 mutant mouse cortex. Cereb Cortex 13:560–571. Stoykova A, Treichel D, Hallonet M, Gruss P. 2000. Pax6 modulates the dorsoventral patterning of the mammalian telencephalon. J Neurosci 20:8042–8050. Stramer B, Moreira S, Millard T, Evans I, Huang CY, Sabet O, Milner M, et al. 2010. Clasp-mediated microtubule bundling regulates persistent motility and contact repulsion in Drosophila macrophages in vivo. J Cell Biol 189:681–689. Stumm RK, Zhou C, Ara T, Lazarini F, Dubois-Dalcq M, Nagasawa T, Hollt V, et al. 2003. CXCR4 regulates interneuron migration in the developing neocortex. J Neurosci 23:5123–5130. Super H, del Rio JA, Martinez A, Perez-Sust P, Soriano E. 2000. Disruption of neuronal migration and radial glia in the developing cerebral cortex following ablation of Cajal-Retzius cells. Cereb Cortex 10:602–613. Super H, Martinez A, del Rio JA, Soriano E. 1998. Involvement of distinct pioneer neurons in the formation of layer-specific connections in the hippocampus. J Neurosci 18:4616–4626. Super H, Martinez A, Soriano E. 1997. Degeneration of Cajal-Retzius cells in the developing cerebral cortex of the mouse after ablation of meningeal cells by 6-hydroxydopamine. Brain Res Dev Brain Res 98:15–20. Tabata H, Nakajima K. 2003. Multipolar migration: The third mode of radial neuronal migration in the developing cerebral cortex. J Neurosci 23:9996–10001. Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RG, Fujisawa H, et al. 1999. Plexinneuropilin-1 complexes form functional semaphorin-3A receptors. Cell 99:59–69.

33

Takiguchi-Hayashi K, Sekiguchi M, Ashigaki S, Takamatsu M, Hasegawa H, Suzuki-Migishima R, Yokoyama M, et al. 2004. Generation of reelin-positive marginal zone cells from the caudomedial wall of telencephalic vesicles. J Neurosci 24:2286–2295. Tamamaki N, Fujimori K, Nojyo Y, Kaneko T, Takauji R. 2003. Evidence that Sema3A and Sema3F regulate the migration of GABAergic neurons in the developing neocortex. J Comp Neurol 455:238–248. Tamamaki N, Nakamura K, Okamoto K, Kaneko T. 2001. Radial glia is a progenitor of neocortical neurons in the developing cerebral cortex. Neurosci Res 41:51–60. Tanaka DH, Maekawa K, Yanagawa Y, Obata K, Murakami F. 2006. Multidirectional and multizonal tangential migration of GABAergic interneurons in the developing cerebral cortex. Development 133:2167– 2176. Tanaka DH, Mikami S, Nagasawa T, Miyazaki J, Nakajima K, Murakami F. 2010. CXCR4 is required for proper regional and laminar distribution of cortical somatostatin-, calretinin-, and neuropeptide Y-expressing GABAergic interneurons. Cereb Cortex 20:2810–2817. Tanaka DH, Nakajima K. 2012. Migratory pathways of GABAergic interneurons when they enter the neocortex. Eur J Neurosci 35:1655–1660. Tashiro K, Tada H, Heilker R, Shirozu M, Nakano T, Honjo T. 1993. Signal sequence trap: a cloning strategy for secreted proteins and type I membrane proteins. Science 261:600–603. Teissier A, Griveau A, Vigier L, Piolot T, Borello U, Pierani A. 2010. A novel transient glutamatergic population migrating from the pallial-subpallial boundary contributes to neocortical development. J Neurosci 30: 10563–10574. Teissier A, Waclaw RR, Griveau A, Campbell K, Pierani A. 2012. Tangentially migrating transient glutamatergic neurons control neurogenesis and maintenance of cerebral cortical progenitor pools. Cereb Cortex 22:403–416. Tissir F, Lambert De RC, Goffinet AM. 2002. The role of reelin in the development and evolution of the cerebral cortex. Braz J Med Biol Res 35:1473–1484. Tissir F, Ravni A, Achouri Y, Riethmacher D, Meyer G, Goffinet AM. 2009. DeltaNp73 regulates neuronal survival in vivo. Proc Natl Acad Sci USA 106:16871– 16876. Tiveron MC, Boutin C, Daou P, Moepps B, Cremer H. 2010. Expression and function of CXCR7 in the mouse forebrain. J Neuroimmunol 224:72–79. Tiveron MC, Rossel M, Moepps B, Zhang YL, Seidenfaden R, Favor J, Konig N, et al. 2006. Molecular interaction between projection neuron precursors and invading interneurons via stromal-derived factor 1.CXCL12./CXCR4 signaling in the cortical subventricular zone/intermediate zone. J Neurosci 26:13273–13278. Tole S, Goudreau G, Assimacopoulos S, Grove EA. 2000. Emx2 is required for growth of the hippocampus but not for hippocampal field specification. J Neurosci 20:2618– 2625. Developmental Neurobiology

34

Barber and Pierani

Toresson H, Potter SS, Campbell K. 2000. Genetic control of dorsal-ventral identity in the telencephalon: Opposing roles for Pax6 and Gsh2. Development 127:4361–4371. Toyofuku T, Yoshida J, Sugimoto T, Yamamoto M, Makino N, Takamatsu H, Takegahara N, et al. 2008. Repulsive and attractive semaphorins cooperate to direct the navigation of cardiac neural crest cells. Dev Biol 321: 251–262. Trousse F, Poluch S, Pierani A, Dutriaux A, Bock HH, Nagasawa T, Verdier JM, et al. 2015. CXCR7 Receptor Controls the Maintenance of Subpial Positioning of Cajal-Retzius Cells. Cereb Cortex 25:3446–3457. Epub 2014 Aug 1. Valentin G, Haas P, Gilmour D. 2007. The chemokine SDF1a coordinates tissue migration through the spatially restricted activation of Cxcr7 and Cxcr4b. Curr Biol 17: 1026–1031. Valverde F, De Carlos JA, Lopez-Mascaraque L. 1995. Time of origin and early fate of preplate cells in the cerebral cortex of the rat. Cereb Cortex 5:483–493. Vasudevan A, Long JE, Crandall JE, Rubenstein JL, Bhide PG. 2008. Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain. Nat Neurosci 11:429–439. Veale KJ, Offenhauser C, Lei N, Stanley AC, Stow JL, Murray RZ. 2011. VAMP3 regulates podosome organisation in macrophages and together with Stx4/SNAP23 mediates adhesion, cell spreading and persistent migration. Exp Cell Res 317:1817–1829. Veale KJ, Offenhauser C, Whittaker SP, Estrella RP, Murray RZ. 2010. Recycling endosome membrane incorporation into the leading edge regulates lamellipodia formation and macrophage migration. Traffic 11:1370– 1379. Venkiteswaran G, Lewellis SW, Wang J, Reynolds E, Nicholson C, Knaut H. 2013. Generation and dynamics of an endogenous, self-generated signaling gradient across a migrating tissue. Cell 155:674–687. Villar-Cervino V, Molano-Mazon M, Catchpole T, Valdeolmillos M, Henkemeyer M, Martinez LM, Borrell V, et al. 2013. Contact repulsion controls the dispersion and final distribution of Cajal-Retzius cells. Neuron 77: 457–471. Walsh C, Cepko CL. 1988. Clonally related cortical cells show several migration patterns. Science 241:1342–1345. Wang WZ, Oeschger FM, Montiel JF, Garcia-Moreno F, Hoerder-Suabedissen A, Krubitzer L, Ek CJ, et al. 2011a. Comparative aspects of subplate zone studied with gene expression in sauropsids and mammals. Cereb Cortex 21: 2187–2203. Wang Y, Li G, Stanco A, Long JE, Crawford D, Potter GB, Pleasure SJ, et al. 2011b. CXCR4 and CXCR7 have distinct functions in regulating interneuron migration. Neuron 69:61–76. Warren N, Caric D, Pratt T, Clausen JA, Asavaritikrai P, Mason JO, Hill RE, et al. 1999. The transcription factor, Pax6, is required for cell proliferation and differentiation in the developing cerebral cortex. Cereb Cortex 9:627–635. Developmental Neurobiology

Welagen J, Anderson S. 2011. Origins of neocortical interneurons in mice. Dev Neurobiol 71:10–17. Wilkinson DG. 2001. Multiple roles of EPH receptors and ephrins in neural development. Nat Rev Neurosci 2:155– 164. Winberg ML, Mitchell KJ, Goodman CS. 1998a. Genetic analysis of the mechanisms controlling target selection: Complementary and combinatorial functions of netrins, semaphorins, and IgCAMs. Cell 93:581–591. Winberg ML, Noordermeer JN, Tamagnone L, Comoglio PM, Spriggs MK, Tessier-Lavigne M, Goodman CS. 1998b. Plexin A is a neuronal semaphorin receptor that controls axon guidance. Cell 95:903–916. Wines-Samuelson M, Handler M, Shen J. 2005. Role of presenilin-1 in cortical lamination and survival of CajalRetzius neurons. Dev Biol 277:332–346. Woo TU, Beale JM, Finlay BL. 1991. Dual fate of subplate neurons in a rodent. Cereb Cortex 1:433–443. Wood JG, Martin S, Price DJ. 1992. Evidence that the earliest generated cells of the murine cerebral cortex form a transient population in the subplate and marginal zone. Brain Res Dev Brain Res 66:137–140. Yabut O, Renfro A, Niu S, Swann JW, Marin O, D’Arcangelo G. 2007. Abnormal laminar position and dendrite development of interneurons in the reeler forebrain. Brain Res 1140:75–83. Yamazaki H, Sekiguchi M, Takamatsu M, Tanabe Y, Nakanishi S. 2004. Distinct ontogenic and regional expressions of newly identified Cajal-Retzius cell-specific genes during neocorticogenesis. Proc Natl Acad Sci USA 101:14509–14514. Yang S, Edman LC, Sanchez-Alcaniz JA, Fritz N, Bonilla S, Hecht J, Uhlen P, et al. 2013. Cxcl12/Cxcr4 signaling controls the migration and process orientation of A9A10 dopaminergic neurons. Development 140:4554– 4564. Yaron A, Huang PH, Cheng HJ, Tessier-Lavigne M. 2005. Differential requirement for Plexin-A3 and -A4 in mediating responses of sensory and sympathetic neurons to distinct class 3 Semaphorins. Neuron 45:513–523. Yokota Y, Eom TY, Stanco A, Kim WY, Rao S, Snider WD, Anton ES. 2010. Cdc42 and Gsk3 modulate the dynamics of radial glial growth, inter-radial glial interactions and polarity in the developing cerebral cortex. Development 137:4101–4110. Yokota Y, Gashghaei HT, Han C, Watson H, Campbell KJ, Anton ES. 2007. Radial glial dependent and independent dynamics of interneuronal migration in the developing cerebral cortex. PLoS One 2:e794 Yoshida K, Gage FH. 1991. Fibroblast growth factors stimulate nerve growth factor synthesis and secretion by astrocytes. Brain Res 538:118–126. Yoshida M, Assimacopoulos S, Jones KR, Grove EA. 2006. Massive loss of Cajal-Retzius cells does not disrupt neocortical layer order. Development 133:537–545. Yun K, Potter S, Rubenstein JL. 2001. Gsh2 and Pax6 play complementary roles in dorsoventral patterning of the mammalian telencephalon. Development 128:193–205.

Tangential Migration of Glutamatergic Neurons Zarbalis K, Choe Y, Siegenthaler JA, Orosco LA, Pleasure SJ. 2012. Meningeal defects alter the tangential migration of cortical interneurons in Foxc1hith/hith mice. Neural Dev 7:2 Zarbalis K, Siegenthaler JA, Choe Y, May SR, Peterson AS, Pleasure SJ. 2007. Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development. Proc Natl Acad Sci USA 104:14002–14007. Zhao C, Guan W, Pleasure SJ. 2006. A transgenic marker mouse line labels Cajal-Retzius cells from the cortical hem and thalamocortical axons. Brain Res 1077:48–53. Zhao C, Kao JP, Kanold PO. 2009. Functional excitatory microcircuits in neonatal cortex connect thalamus and layer 4. J Neurosci 29:15479–15488. Zhao Y, Kwan KM, Mailloux CM, Lee WK, Grinberg A, Wurst W, Behringer RR, et al. 2007. LIM-homeodomain

35

proteins Lhx1 and Lhx5, and their cofactor Ldb1, control Purkinje cell differentiation in the developing cerebellum. Proc Natl Acad Sci USA 104:13182–13186. Zhou FM, Hablitz JJ. 1996. Layer I neurons of the rat neocortex. II. Voltage-dependent outward currents. J Neurophysiol 76:668–682. Zhu Y, Yu T, Zhang XC, Nagasawa T, Wu JY, Rao Y. 2002. Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons. Nat Neurosci 5:719–720. Zimmer C, Lee J, Griveau A, Arber S, Pierani A, Garel S, Guillemot F. 2010. Role of Fgf8 signalling in the specification of rostral Cajal-Retzius cells. Development 137: 293–302. Zylbersztejn K, Petkovic M, Burgo A, Deck M, Garel S, Marcos S, Bloch-Gallego E, et al. 2012. The vesicular SNARE Synaptobrevin is required for Semaphorin 3A axonal repulsion. J Cell Biol 196:37–46.

Developmental Neurobiology

Tangential migration of neuronal precursors of glutamatergic neurons in the adult mammalian brain.

Longitudinal RNA sequencing of the deep transcriptome during neurogenesis of cortical glutamatergic neurons from murine ESCs.

N-cadherin sustains motility and polarity of future cortical interneurons during tangential migration.

Coordinated Plasticity between Barrel Cortical Glutamatergic and GABAergic Neurons during Associative Memory.

Migration dynamics, entrepreneurship, and African development: Lessons from Malawi.

Cdk5 phosphorylation of ErbB4 is required for tangential migration of cortical interneurons.

Engineering Hematopoietic Stem Cells: Lessons from Development.

Nephron Patterning: Lessons from Xenopus, Zebrafish, and Mouse Studies.

Synergistic regulation of glutamatergic transmission by serotonin and norepinephrine reuptake inhibitors in prefrontal cortical neurons.

Hippocampal pyramidal neurons switch from a multipolar migration mode to a novel "climbing" migration mode during development.

Interleukin-1 beta guides the migration of cortical neurons.

Slow potentials and spike activity of cortical neurons during development of internal inhibition.

Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development.

Corrigendum: Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development.

Impulse activity and the patterning of connections during CNS development.

Glutamatergic stimulation induces GluN2B translation by the nitric oxide-Heme-Regulated eIF2α kinase in cortical neurons.

Bcl-2 proteins, cell migration and embryonic development: lessons from zebrafish.

Development and migration of avian sympathetic preganglionic neurons.

Osteopontin improves adhesion and migration of human primary renal cortical epithelial cells during wound healing.

Germ line development: lessons learned from pluripotent stem cells.

Control of cerebrovascular patterning by neural activity during postnatal development.

Connexins in migration during development and cancer.

Biology of normal luteinizing hormone-releasing hormone neurons during and after their migration from olfactory placode.

Nutrition and health development--lessons from Kerala.