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Figure 1. Compound eyes of a starfish and a crustacean. (A) The eye of the starfish Linckia laevigata showing ommatidia without lenses in a loose irregular structure. Height 0.6 mm. (Reproduced with permission from [1].) (B) Eye of a hermit crab Pagurus excavatus showing ommatidia with complex optics in a tight hexagonal structure. Height 2 mm. (Courtesy of Dan-Eric Nilsson.)
filter feeders. If we compare them to the three major groups that have attained multipurpose vision, we find that what the latter have in common is a relatively large brain, and within that brain a huge proportion devoted to vision: rough estimates are 60% for man, 79% for a fly and 67% for an octopus [2]. In computational terms, sophisticated vision is not cheap. Typically such brains have partially separate pathways for pattern and for motion (corresponding roughly to the ventral and dorsal cortical streams in man [6]). This combination of mechanisms for recognition and for locomotor control presumably arose in all three lineages in the melting pot of the Cambrian. Thereafter it has been sufficiently adaptable to
enable animals — in two of the three groups — to cope with life on land, and eventually with flight. In contrast, none of the animals with single-purpose vision has a particularly large brain, nor a high proportion devoted to vision. Nilsson [7] has described vision in animals as arising in four evolutionary stages: first, simple photoreception; second, photoreception with some degree of directionality allowing basic phototaxis; third, low-resolution spatial vision; and fourth, high-resolution multipurpose vision. The starfish studied by Garm and Nilsson [1] fit firmly into the third category: they have spatial vision good enough to allow them to navigate towards large dark objects, but are probably used for little else. This third category is in a way the
Genetics: A Common Origin for Neuronal Asymmetries? A new study reveals an unexpected genetic link between two distinct types of neuronal asymmetries in the nematode Caenorhabditis elegans. This finding suggests a common origin of genetically determined asymmetries and raises intriguing questions about their evolution. Iskra A. Signore1,2 and Miguel L. Concha1,2,* The nervous system of most animals is overall bilaterally symmetric.
However, a number of neural circuits show distinct proportions and/or types of neurons on the left and right sides [1]. Several types of neural asymmetries normally co-exist in an
most heterogeneous and problematic. It contains animals as diverse as cubomedusan jellyfish which use low resolution vision to maintain station in water currents, copepods with tiny eyes that use vision for finding mates, and others such as Nautilus which has retained a very inefficient pinhole eye while its cephalopod relatives evolved excellent lens eyes [4]. In all these cases vision seems to have got stuck at some evolutionary stage, either because the animals had no need for better eyesight, or because their brains were not initially configured in a way that allowed it. It is something of a chicken and egg problem: did lack of visual capacity hold back behaviour, or was it the other way round? References 1. Garm, A., and Nilsson, D.-E. (2014). Visual navigation in starfish: first evidence for the use of vision and eyes in starfish. Proc. R. Soc. Lond. B 281, 20133011. 2. Land, M.F., and Nilsson, D.-E. (2006). General-purpose and special-purpose visual systems. In Invertebrate Vision, E. Warrant and D.-E. Nilsson, eds. (Cambridge: Cambridge University Press), pp. 167–210. 3. Nilsson, D.-E. (1994). Eyes as optical alarm systems in fan worms and ark clams. Phil. Trans. R. Soc. Lond. B 346, 195–212. 4. Land, M.F., and Nilsson, D.-E. (2012). Animal Eyes, 2nd ed (Oxford: Oxford University Press). 5. Land, M.F. (1982). Scanning eye movements in a heteropod mollusc. J. Exp. Biol. 96, 427–430. 6. Milner, A.D., and Goodale, M.A. (2006). The Visual Brain in Action, 2nd ed. (Oxford: Oxford University Press). 7. Nilsson, D.-E. (2009). The evolution of eyes and visually guided behaviour. Phil. Trans. R. Soc. Lond. B 364, 2833–2847.
School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK. E-mail: [email protected]
http://dx.doi.org/10.1016/j.cub.2014.01.032
individual of a particular species. For example, humans exhibit circuit asymmetries within ascending (sensorial), descending (motor) and higher-order (associational and commissural) pathways [2], while various types of neuronal asymmetries are observed in the nervous system of Caenorhabditis elegans [3]. A recent study by Cochella et al. [4] has addressed whether — and to what extent — different types of neural asymmetries are linked in their origin by providing the first demonstration of a genetic link
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Figure 1. Linking neuronal asymmetries. (A–D) Different types of asymmetries can be linked by biased circuit use (A), biased cellular morphogenesis (B) and through lateralised genetic control, which either couples the handedness of directional asymmetries (C) or links a directional asymmetry to an antisymmetry (D). (A’–D’) Examples of the different forms of asymmetry linkage depicted in A–D. (A’) Asymmetries in motoneuron size (green circles) and sensory axon number (blue lines) in the first thoracic ganglia are coupled by the appearance of a larger chela (red) in male fiddler crabs. (B’) In zebrafish, a biased process of cell migration (red arrows) links the asymmetric positioning and connectivity of the parapineal nucleus (green) with asymmetric development of habenular neurons (L-type neurons are depicted as blue circles). (C’) The direction of epithalamic (parapineal and habenulae in blue) and visceral (heart and pancreas in green) asymmetries is coupled by the asymmetric expression of Nodal signalling on the left side of the zebrafish embryo (red). (D’) In worms, the asymmetric activity of die-1 (in red, top panel) links the antisymmetric development of AWC olfactory neurons to the directional asymmetry of ASE gustatory neurons. In the bottom panel, AWCON and AWCOFF are depicted in filled and empty green circles, while ASEL and ASER are shown as filled and empty blue circles, respectively. Top and bottom panels refer to early and late phases of the asymmetry specification and linking process. References and details are given in the text.
between two distinct types of neuronal asymmetries in worms. There are different means by which asymmetries of different neuronal populations could be linked (Figure 1). One way is by the biased use of a neuronal circuit due to a lateralised sensorimotor experience, which results in asymmetric morphological changes of specific neurons (Figure 1A). For instance, male and female fiddler crabs form a pair of chelae that are initially symmetric. However, in males, one of the two chela becomes enlarged during a critical period of ontogeny. As a consequence, asymmetries of the first thoracic ganglia appear on the side of the major chela, linking the development of hypertrophy of the motoneurons with hyperplasia of the sensory neurons (Figure 1A’) [5].
Asymmetries of two distinct neuronal populations may also be linked through a lateralised cellular morphogenetic process, where there is a transfer of asymmetry from one neuronal population to another (Figure 1B). For example, the parapineal nucleus of zebrafish is specified at the dorsal midline of the brain and undergoes asymmetric migration to the left side. There it promotes the elaboration of neuronal asymmetries in the left habenula. As a consequence, left and right habenular nuclei develop distinct amounts of L-type and R-type neurons (Figure 1B’). The removal of the parapineal nucleus prior to its asymmetric migration consequently results in symmetrisation of habenular neuron development [6–8]. Another way of linking asymmetries is by sharing a common genetic
control. Genetically determined asymmetries may come in two forms. They can show a preferential bias within the population (directional asymmetries) or may be randomly distributed by a mechanism of antisymmetry [9]. Until now, examples of asymmetries linked by a common genetic control were restricted to the coordination of directional asymmetries: a shared genetic signal can confer a common laterality cue to independently generated asymmetries, resulting in directional asymmetries with consistent and coordinated handedness (Figure 1C). For example, the Nodal signalling pathway is expressed asymmetrically on the left side of the zebrafish embryo, particularly within left-sided precursors of both dorsal diencephalic neurons and visceral organs such as the heart and pancreas [10].
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Asymmetric Nodal signalling is not required for asymmetric development per se but is needed to bias the direction of neuronal and visceral asymmetries in a coordinated manner towards the left side of the embryo (Figure 1C’). Consequently, in the absence of asymmetric Nodal signalling, handedness of neuronal and visceral asymmetries is determined independently and becomes randomised within the population, with equal proportions of left- and right-sided neuronal and visceral asymmetric phenotypes [11]. The recent paper by Cochella et al. [4] extends the notion of a shared genetic control, providing the first example of a genetic factor that links directional and antisymmetric neuronal asymmetries in an animal (Figure 1D). In C. elegans, ASE and AWC are two bilateral pairs of neurons that appear symmetric with respect to morphology but show distinct patterns of asymmetric chemoreceptor expression that are fundamental for the discrimination of sensorial stimuli [12,13]. The ASE gustatory neuron pair shows a directional asymmetric expression of different types of chemoreceptors of the receptor-type guanylyl cyclase (gyc) family, with the left neuron (ASEL) expressing gyc-7 and the right neuron (ASER) expressing gyc-5 [14,15]. The AWC olfactory neuron pair, however, exhibits an antisymmetric, anti-correlated, left–right asymmetric pattern of expression of different olfactory G-protein-coupled receptors (GPCRs), with the neuron of one side expressing srsx-3 (called AWCOFF) while the contralateral expresses str-2 (called AWCON) (Figure 1D’) [16,17]. ASE and AWC asymmetries are supposed to be controlled by independent genetic mechanisms but the paper of Cochella et al. [4] demonstrates that these asymmetries are linked by the activity of die-1, a zinc finger transcription factor. die-1 has a role in the asymmetric development of both neuronal types. In ASE neurons, die-1 is expressed with a left-sided directional bias, while in AWC neurons, it shows an antisymmetric expression (Figure 1D’). The functional loss of die-1 results in symmetric development of both ASE and AWC, which results in the specification of two ASER and two
AWCON neuron pairs. Conversely, bilateral symmetric expression of die-1 results in the development of two ASEL and two AWCOFF neuron pairs. Therefore, die-1 is both required and sufficient for the development of ASE directional asymmetry and AWC antisymmetry, promoting ASEL and AWCOFF neuronal fates. Cochella et al. [4] also demonstrated that die-1 works in a contextdependent manner after the initial symmetry-breaking event in both neuron types. In ASE neurons, die-1 works as an output of the bi-stable loop that determines the directional asymmetric expression of gyc genes, while in AWC it controls a pathway parallel to the previously described Ca+2-dependent mitogen-activated protein kinase (MAPK)-type pathway to regulate the antisymmetric expression, of olfactory GPCRs [4,18,19]. The context-dependent function of die-1 was revealed at two different levels. First, distinct cis-regulatory elements control the directional asymmetric expression of die-1 in ASE and its antisymmetric expression in AWC neurons. Second, as a transcription factor, die-1 targets different genes in both neuron types. The origin and meaning of such context dependency remains unclear, as well as the possible extension of the die-1 genetic link to other types of neuronal asymmetries in C. elegans. Two different cis-regulatory regions located upstream of the die-1 locus and in the 3’ untranslated region (UTR) have the ability to promote die-1 expression in ASEL neurons and repress die-1 expression in the contralateral ASER neurons, respectively. Intriguingly, although both regulatory regions seem sufficient to regulate die-1 expression, only the former is necessary during normal asymmetric development of ASE neurons [4,20]. The meaning of this finding is unclear but it might relate to the evolution of directional asymmetries in C. elegans. Future comparative analysis among divergent nematode species will help to address this question and also a possible role of die-1 in the evolution of asymmetry. It has been proposed that directional asymmetries can evolve from ancestral forms of antisymmetry, in which one of the two random asymmetric configurations becomes
fixed within the population [9]. The findings of Cochella et al. [4] thus provide the opportunity to test this hypothesis and gain mechanistic insights into the evolution of asymmetries in worms. References 1. Concha, M.L., Bianco, I.H., and Wilson, S.W. (2012). Encoding asymmetry within neural circuits. Nat. Rev. Neurosci. 13, 832–843. 2. Hugdahl, K., and Westerfield, M. (2010). The Two Halves of the Brain. Information Processing in the Cerebral Hemispheres (London, England: MIT Press). 3. Hobert, O., Johnston, R.J., Jr., and Chang, S. (2002). Left-right asymmetry in the nervous system: the Caenorhabditis elegans model. Nat. Rev. Neurosci. 3, 629–640. 4. Cochella, L., Tursun, B., Hsieh, Y.-W., Galindo, S., Johnston, R.J., Chuang, C.-F., and Hobert, O. (2014). Two distinct types of neuronal asymmetries are controlled by the Caenorhabditis elegans zinc finger transcription factor die-1. Genes Dev. 28, 34–43. 5. Young, R.E., and Govind, C.K. (1983). Neural asymmetry in male fiddler crabs. Brain Res. 280, 251–262. 6. Concha, M.L., Russell, C., Regan, J.C., Tawk, M., Sidi, S., Gilmour, D.T., Kapsimali, M., Sumoy, L., Goldstone, K., Amaya, E., et al. (2003). Local tissue interactions across the dorsal midline of the forebrain establish CNS laterality. Neuron 39, 423–438. 7. Bianco, I.H., Carl, M., Russell, C., Clarke, J.D., and Wilson, S.W. (2008). Brain asymmetry is encoded at the level of axon terminal morphology. Neural Dev. 3, 9. 8. Gamse, J.T., Thisse, C., Thisse, B., and Halpern, M.E. (2003). The parapineal mediates left-right asymmetry in the zebrafish diencephalon. Development 130, 1059–1068. 9. Palmer, A.R. (2004). Symmetry breaking and the evolution of development. Science 306, 828–833. 10. Bisgrove, B.W., Essner, J.J., and Yost, H.J. (2000). Multiple pathways in the midline regulate concordant brain, heart and gut left-right asymmetry. Development 127, 3567–3579. 11. Concha, M.L., Burdine, R.D., Russell, C., Schier, A.F., and Wilson, S.W. (2000). A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain. Neuron 28, 399–409. 12. Ortiz, C.O., Faumont, S., Takayama, J., Ahmed, H.K., Goldsmith, A.D., Pocock, R., McCormick, K.E., Kunimoto, H., Iino, Y., Lockery, S., et al. (2009). Lateralized gustatory behavior of C. elegans is controlled by specific receptor-type guanylyl cyclases. Curr. Biol. 19, 996–1004. 13. Wes, P.D., and Bargmann, C.I. (2001). C. elegans odour discrimination requires asymmetric diversity in olfactory neurons. Nature 410, 698–701. 14. Yu, S., Avery, L., Baude, E., and Garbers, D.L. (1997). Guanylyl cyclase expression in specific sensory neurons: a new family of chemosensory receptors. Proc. Natl. Acad. Sci. USA 94, 3384–3387. 15. Ortiz, C.O., Etchberger, J.F., Posy, S.L., Frokjaer-Jensen, C., Lockery, S., Honig, B., and Hobert, O. (2006). Searching for neuronal left/ right asymmetry: genomewide analysis of nematode receptor-type guanylyl cyclases. Genetics 173, 131–149. 16. Troemel, E.R., Sagasti, A., and Bargmann, C.I. (1999). Lateral signaling mediated by axon contact and calcium entry regulates asymmetric odorant receptor expression in C. elegans. Cell 99, 387–398.
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17. Bauer Huang, S.L., Saheki, Y., VanHoven, M.K., Torayama, I., Ishihara, T., Katsura, I., van der Linden, A., Sengupta, P., and Bargmann, C.I. (2007). Left-right olfactory asymmetry results from antagonistic functions of voltageactivated calcium channels and the Raw repeat protein OLRN-1 in C. elegans. Neural Dev. 2, 24. 18. Sagasti, A., Hisamoto, N., Hyodo, J., TanakaHino, M., Matsumoto, K., and Bargmann, C.I. (2001). The CaMKII UNC-43 activates the MAPKKK NSY-1 to execute a lateral signaling
decision required for asymmetric olfactory neuron fates. Cell 105, 221–232. 19. Hobert, O. (2006). Architecture of a microRNA-controlled gene regulatory network that diversifies neuronal cell fates. Cold Spring Harb. Symp. Quant. Biol. 71, 181–188. 20. Didiano, D., Cochella, L., Tursun, B., and Hobert, O. (2010). Neuron-type specific regulation of a 3’UTR through redundant and combinatorially acting cis-regulatory elements. RNA 16, 349–363.
Visual Neuroscience: A Binocular Advantage for Word Processing during Reading A recent study using a novel saccade-contingent display-change technique to control the presentation of text to each eye shows a binocular advantage for both foveal and parafoveal processing of words during natural reading. Kevin Paterson Being able to read is crucial for functioning effectively in everyday life. Most individuals read binocularly; consequently, for the vast majority of individuals, normal reading requires the precisely coordinated rotation of the two eyes so that the eyes make conjugate saccadic movements along lines of text. These saccades tend to be relatively short, lasting approximately 20–30 ms and spanning about 7–9 letters, roughly 2 of visual angle, when silently reading in alphabetic languages like English [1–3]. Each eye movement ends in a brief fixational pause (averaging 250–300 ms), during which both eyes acquire visual information that is used rapidly to establish the identity of individual words in the text. Variability in the length of these fixational pauses reflects the ease with which words can be identified, and words that are more familiar to the reader typically will receive shorter fixations. The length of the fixational pauses is therefore sensitive to cognitive processes that underlie the real-time recognition of words during reading. The superiority of binocular over monocular viewing has been demonstrated in a range of non-reading tasks, and this binocular advantage is attributed to the neural summation of the visual input to each eye [4,5]. However, the importance of binocular viewing for reading has largely been overlooked;
indeed, it is only very recently that researchers have examined the role of the two eyes in reading, focusing on the efficiency with which the oculomotor system coordinates saccadic eye movements [6–8]. This research has shown that locations of the two eyes’ fixations are generally well-coordinated and that the average disparity in these locations is less than the span of two character spaces for skilled adult readers, although on rare occasions the eyes fixate locations that are much further apart, sometimes even on different words in a sentence. There are, however, indications of a binocular advantage in reading from research showing that the coordination of the two eyes differs during binocular compared to monocular reading and that fixational pauses are shorter during binocular reading [9]. As they report in this issue of Current Biology, Jainta et al. [10] addressed this issue more fully using a novel saccade-contingent displaychange technique in which the presentation of text was either monocular or binocular throughout reading, or precisely controlled using high-speed shutter glasses so that the presentation changed from binocular to monocular (or vice versa) in real-time, triggered by the reader making a saccade that crossed an invisible boundary in the text. Participants were unaware of this change but, as I will explain in more detail below, the duration of
1Anatomy
and Developmental Biology Program, Institute of Biomedical Sciences, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile. 2Biomedical Neuroscience Institute, Santiago 8380453, Chile. *E-mail: [email protected] http://dx.doi.org/10.1016/j.cub.2014.01.031
fixational pauses on a designated target word in each sentence showed that the usual advantage for more familiar words was obtained during binocular, but not monocular, presentations. This led Jainta et al. [10] to conclude that denial of a unified visual signal derived from binocular inputs disrupts the lexical processing of words and thereby impairs the normal efficiency of reading. A central concern for eye movement research has been to establish what eye movements can reveal about the underlying cognitive processes in reading. A substantial body of evidence ([11,12], for reviews, see [1,2]), supported by computational models of eye movement control during reading [13–15], shows that the duration of fixational pauses on words is sensitive to the ease with which words can be identified. The familiarity of a word to the reader is of particular importance to this process. Indeed, a fundamental assumption of the E-Z Reader model [14,15] is that the decision about when to move the eyes during reading is governed by a process that establishes whether a word is familiar and so likely to be identified imminently. A reader’s eyes usually will dwell for momentarily longer on words that have a lower frequency of usage in text and so are less familiar to the reader. This difference in the length of fixational pauses for words with a higher rather than lower frequency of usage is described as the word frequency effect and is considered to be a hallmark of lexical processing during reading [1,2]. Disruption to the word frequency effect is associated with impairment to the normal process of word identification, and typically is observed when the visual quality of text is degraded [16–18]. For this reason, Jainta et al. [10] used the word frequency effect as a diagnostic of the efficiency of processing word identity during
Figure 1. Compound eyes of a starfish and a crustacean. (A) The eye of the starfish Linckia laevigata showing ommatidia without lenses in a loose irregular structure. Height 0.6 mm. (Reproduced with permission from [1].) (B) Eye of a hermit crab Pagurus excavatus showing ommatidia with complex optics in a tight hexagonal structure. Height 2 mm. (Courtesy of Dan-Eric Nilsson.)
filter feeders. If we compare them to the three major groups that have attained multipurpose vision, we find that what the latter have in common is a relatively large brain, and within that brain a huge proportion devoted to vision: rough estimates are 60% for man, 79% for a fly and 67% for an octopus [2]. In computational terms, sophisticated vision is not cheap. Typically such brains have partially separate pathways for pattern and for motion (corresponding roughly to the ventral and dorsal cortical streams in man [6]). This combination of mechanisms for recognition and for locomotor control presumably arose in all three lineages in the melting pot of the Cambrian. Thereafter it has been sufficiently adaptable to
enable animals — in two of the three groups — to cope with life on land, and eventually with flight. In contrast, none of the animals with single-purpose vision has a particularly large brain, nor a high proportion devoted to vision. Nilsson [7] has described vision in animals as arising in four evolutionary stages: first, simple photoreception; second, photoreception with some degree of directionality allowing basic phototaxis; third, low-resolution spatial vision; and fourth, high-resolution multipurpose vision. The starfish studied by Garm and Nilsson [1] fit firmly into the third category: they have spatial vision good enough to allow them to navigate towards large dark objects, but are probably used for little else. This third category is in a way the
Genetics: A Common Origin for Neuronal Asymmetries? A new study reveals an unexpected genetic link between two distinct types of neuronal asymmetries in the nematode Caenorhabditis elegans. This finding suggests a common origin of genetically determined asymmetries and raises intriguing questions about their evolution. Iskra A. Signore1,2 and Miguel L. Concha1,2,* The nervous system of most animals is overall bilaterally symmetric.
However, a number of neural circuits show distinct proportions and/or types of neurons on the left and right sides [1]. Several types of neural asymmetries normally co-exist in an
most heterogeneous and problematic. It contains animals as diverse as cubomedusan jellyfish which use low resolution vision to maintain station in water currents, copepods with tiny eyes that use vision for finding mates, and others such as Nautilus which has retained a very inefficient pinhole eye while its cephalopod relatives evolved excellent lens eyes [4]. In all these cases vision seems to have got stuck at some evolutionary stage, either because the animals had no need for better eyesight, or because their brains were not initially configured in a way that allowed it. It is something of a chicken and egg problem: did lack of visual capacity hold back behaviour, or was it the other way round? References 1. Garm, A., and Nilsson, D.-E. (2014). Visual navigation in starfish: first evidence for the use of vision and eyes in starfish. Proc. R. Soc. Lond. B 281, 20133011. 2. Land, M.F., and Nilsson, D.-E. (2006). General-purpose and special-purpose visual systems. In Invertebrate Vision, E. Warrant and D.-E. Nilsson, eds. (Cambridge: Cambridge University Press), pp. 167–210. 3. Nilsson, D.-E. (1994). Eyes as optical alarm systems in fan worms and ark clams. Phil. Trans. R. Soc. Lond. B 346, 195–212. 4. Land, M.F., and Nilsson, D.-E. (2012). Animal Eyes, 2nd ed (Oxford: Oxford University Press). 5. Land, M.F. (1982). Scanning eye movements in a heteropod mollusc. J. Exp. Biol. 96, 427–430. 6. Milner, A.D., and Goodale, M.A. (2006). The Visual Brain in Action, 2nd ed. (Oxford: Oxford University Press). 7. Nilsson, D.-E. (2009). The evolution of eyes and visually guided behaviour. Phil. Trans. R. Soc. Lond. B 364, 2833–2847.
School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK. E-mail: [email protected]
http://dx.doi.org/10.1016/j.cub.2014.01.032
individual of a particular species. For example, humans exhibit circuit asymmetries within ascending (sensorial), descending (motor) and higher-order (associational and commissural) pathways [2], while various types of neuronal asymmetries are observed in the nervous system of Caenorhabditis elegans [3]. A recent study by Cochella et al. [4] has addressed whether — and to what extent — different types of neural asymmetries are linked in their origin by providing the first demonstration of a genetic link
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Figure 1. Linking neuronal asymmetries. (A–D) Different types of asymmetries can be linked by biased circuit use (A), biased cellular morphogenesis (B) and through lateralised genetic control, which either couples the handedness of directional asymmetries (C) or links a directional asymmetry to an antisymmetry (D). (A’–D’) Examples of the different forms of asymmetry linkage depicted in A–D. (A’) Asymmetries in motoneuron size (green circles) and sensory axon number (blue lines) in the first thoracic ganglia are coupled by the appearance of a larger chela (red) in male fiddler crabs. (B’) In zebrafish, a biased process of cell migration (red arrows) links the asymmetric positioning and connectivity of the parapineal nucleus (green) with asymmetric development of habenular neurons (L-type neurons are depicted as blue circles). (C’) The direction of epithalamic (parapineal and habenulae in blue) and visceral (heart and pancreas in green) asymmetries is coupled by the asymmetric expression of Nodal signalling on the left side of the zebrafish embryo (red). (D’) In worms, the asymmetric activity of die-1 (in red, top panel) links the antisymmetric development of AWC olfactory neurons to the directional asymmetry of ASE gustatory neurons. In the bottom panel, AWCON and AWCOFF are depicted in filled and empty green circles, while ASEL and ASER are shown as filled and empty blue circles, respectively. Top and bottom panels refer to early and late phases of the asymmetry specification and linking process. References and details are given in the text.
between two distinct types of neuronal asymmetries in worms. There are different means by which asymmetries of different neuronal populations could be linked (Figure 1). One way is by the biased use of a neuronal circuit due to a lateralised sensorimotor experience, which results in asymmetric morphological changes of specific neurons (Figure 1A). For instance, male and female fiddler crabs form a pair of chelae that are initially symmetric. However, in males, one of the two chela becomes enlarged during a critical period of ontogeny. As a consequence, asymmetries of the first thoracic ganglia appear on the side of the major chela, linking the development of hypertrophy of the motoneurons with hyperplasia of the sensory neurons (Figure 1A’) [5].
Asymmetries of two distinct neuronal populations may also be linked through a lateralised cellular morphogenetic process, where there is a transfer of asymmetry from one neuronal population to another (Figure 1B). For example, the parapineal nucleus of zebrafish is specified at the dorsal midline of the brain and undergoes asymmetric migration to the left side. There it promotes the elaboration of neuronal asymmetries in the left habenula. As a consequence, left and right habenular nuclei develop distinct amounts of L-type and R-type neurons (Figure 1B’). The removal of the parapineal nucleus prior to its asymmetric migration consequently results in symmetrisation of habenular neuron development [6–8]. Another way of linking asymmetries is by sharing a common genetic
control. Genetically determined asymmetries may come in two forms. They can show a preferential bias within the population (directional asymmetries) or may be randomly distributed by a mechanism of antisymmetry [9]. Until now, examples of asymmetries linked by a common genetic control were restricted to the coordination of directional asymmetries: a shared genetic signal can confer a common laterality cue to independently generated asymmetries, resulting in directional asymmetries with consistent and coordinated handedness (Figure 1C). For example, the Nodal signalling pathway is expressed asymmetrically on the left side of the zebrafish embryo, particularly within left-sided precursors of both dorsal diencephalic neurons and visceral organs such as the heart and pancreas [10].
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Asymmetric Nodal signalling is not required for asymmetric development per se but is needed to bias the direction of neuronal and visceral asymmetries in a coordinated manner towards the left side of the embryo (Figure 1C’). Consequently, in the absence of asymmetric Nodal signalling, handedness of neuronal and visceral asymmetries is determined independently and becomes randomised within the population, with equal proportions of left- and right-sided neuronal and visceral asymmetric phenotypes [11]. The recent paper by Cochella et al. [4] extends the notion of a shared genetic control, providing the first example of a genetic factor that links directional and antisymmetric neuronal asymmetries in an animal (Figure 1D). In C. elegans, ASE and AWC are two bilateral pairs of neurons that appear symmetric with respect to morphology but show distinct patterns of asymmetric chemoreceptor expression that are fundamental for the discrimination of sensorial stimuli [12,13]. The ASE gustatory neuron pair shows a directional asymmetric expression of different types of chemoreceptors of the receptor-type guanylyl cyclase (gyc) family, with the left neuron (ASEL) expressing gyc-7 and the right neuron (ASER) expressing gyc-5 [14,15]. The AWC olfactory neuron pair, however, exhibits an antisymmetric, anti-correlated, left–right asymmetric pattern of expression of different olfactory G-protein-coupled receptors (GPCRs), with the neuron of one side expressing srsx-3 (called AWCOFF) while the contralateral expresses str-2 (called AWCON) (Figure 1D’) [16,17]. ASE and AWC asymmetries are supposed to be controlled by independent genetic mechanisms but the paper of Cochella et al. [4] demonstrates that these asymmetries are linked by the activity of die-1, a zinc finger transcription factor. die-1 has a role in the asymmetric development of both neuronal types. In ASE neurons, die-1 is expressed with a left-sided directional bias, while in AWC neurons, it shows an antisymmetric expression (Figure 1D’). The functional loss of die-1 results in symmetric development of both ASE and AWC, which results in the specification of two ASER and two
AWCON neuron pairs. Conversely, bilateral symmetric expression of die-1 results in the development of two ASEL and two AWCOFF neuron pairs. Therefore, die-1 is both required and sufficient for the development of ASE directional asymmetry and AWC antisymmetry, promoting ASEL and AWCOFF neuronal fates. Cochella et al. [4] also demonstrated that die-1 works in a contextdependent manner after the initial symmetry-breaking event in both neuron types. In ASE neurons, die-1 works as an output of the bi-stable loop that determines the directional asymmetric expression of gyc genes, while in AWC it controls a pathway parallel to the previously described Ca+2-dependent mitogen-activated protein kinase (MAPK)-type pathway to regulate the antisymmetric expression, of olfactory GPCRs [4,18,19]. The context-dependent function of die-1 was revealed at two different levels. First, distinct cis-regulatory elements control the directional asymmetric expression of die-1 in ASE and its antisymmetric expression in AWC neurons. Second, as a transcription factor, die-1 targets different genes in both neuron types. The origin and meaning of such context dependency remains unclear, as well as the possible extension of the die-1 genetic link to other types of neuronal asymmetries in C. elegans. Two different cis-regulatory regions located upstream of the die-1 locus and in the 3’ untranslated region (UTR) have the ability to promote die-1 expression in ASEL neurons and repress die-1 expression in the contralateral ASER neurons, respectively. Intriguingly, although both regulatory regions seem sufficient to regulate die-1 expression, only the former is necessary during normal asymmetric development of ASE neurons [4,20]. The meaning of this finding is unclear but it might relate to the evolution of directional asymmetries in C. elegans. Future comparative analysis among divergent nematode species will help to address this question and also a possible role of die-1 in the evolution of asymmetry. It has been proposed that directional asymmetries can evolve from ancestral forms of antisymmetry, in which one of the two random asymmetric configurations becomes
fixed within the population [9]. The findings of Cochella et al. [4] thus provide the opportunity to test this hypothesis and gain mechanistic insights into the evolution of asymmetries in worms. References 1. Concha, M.L., Bianco, I.H., and Wilson, S.W. (2012). Encoding asymmetry within neural circuits. Nat. Rev. Neurosci. 13, 832–843. 2. Hugdahl, K., and Westerfield, M. (2010). The Two Halves of the Brain. Information Processing in the Cerebral Hemispheres (London, England: MIT Press). 3. Hobert, O., Johnston, R.J., Jr., and Chang, S. (2002). Left-right asymmetry in the nervous system: the Caenorhabditis elegans model. Nat. Rev. Neurosci. 3, 629–640. 4. Cochella, L., Tursun, B., Hsieh, Y.-W., Galindo, S., Johnston, R.J., Chuang, C.-F., and Hobert, O. (2014). Two distinct types of neuronal asymmetries are controlled by the Caenorhabditis elegans zinc finger transcription factor die-1. Genes Dev. 28, 34–43. 5. Young, R.E., and Govind, C.K. (1983). Neural asymmetry in male fiddler crabs. Brain Res. 280, 251–262. 6. Concha, M.L., Russell, C., Regan, J.C., Tawk, M., Sidi, S., Gilmour, D.T., Kapsimali, M., Sumoy, L., Goldstone, K., Amaya, E., et al. (2003). Local tissue interactions across the dorsal midline of the forebrain establish CNS laterality. Neuron 39, 423–438. 7. Bianco, I.H., Carl, M., Russell, C., Clarke, J.D., and Wilson, S.W. (2008). Brain asymmetry is encoded at the level of axon terminal morphology. Neural Dev. 3, 9. 8. Gamse, J.T., Thisse, C., Thisse, B., and Halpern, M.E. (2003). The parapineal mediates left-right asymmetry in the zebrafish diencephalon. Development 130, 1059–1068. 9. Palmer, A.R. (2004). Symmetry breaking and the evolution of development. Science 306, 828–833. 10. Bisgrove, B.W., Essner, J.J., and Yost, H.J. (2000). Multiple pathways in the midline regulate concordant brain, heart and gut left-right asymmetry. Development 127, 3567–3579. 11. Concha, M.L., Burdine, R.D., Russell, C., Schier, A.F., and Wilson, S.W. (2000). A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain. Neuron 28, 399–409. 12. Ortiz, C.O., Faumont, S., Takayama, J., Ahmed, H.K., Goldsmith, A.D., Pocock, R., McCormick, K.E., Kunimoto, H., Iino, Y., Lockery, S., et al. (2009). Lateralized gustatory behavior of C. elegans is controlled by specific receptor-type guanylyl cyclases. Curr. Biol. 19, 996–1004. 13. Wes, P.D., and Bargmann, C.I. (2001). C. elegans odour discrimination requires asymmetric diversity in olfactory neurons. Nature 410, 698–701. 14. Yu, S., Avery, L., Baude, E., and Garbers, D.L. (1997). Guanylyl cyclase expression in specific sensory neurons: a new family of chemosensory receptors. Proc. Natl. Acad. Sci. USA 94, 3384–3387. 15. Ortiz, C.O., Etchberger, J.F., Posy, S.L., Frokjaer-Jensen, C., Lockery, S., Honig, B., and Hobert, O. (2006). Searching for neuronal left/ right asymmetry: genomewide analysis of nematode receptor-type guanylyl cyclases. Genetics 173, 131–149. 16. Troemel, E.R., Sagasti, A., and Bargmann, C.I. (1999). Lateral signaling mediated by axon contact and calcium entry regulates asymmetric odorant receptor expression in C. elegans. Cell 99, 387–398.
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17. Bauer Huang, S.L., Saheki, Y., VanHoven, M.K., Torayama, I., Ishihara, T., Katsura, I., van der Linden, A., Sengupta, P., and Bargmann, C.I. (2007). Left-right olfactory asymmetry results from antagonistic functions of voltageactivated calcium channels and the Raw repeat protein OLRN-1 in C. elegans. Neural Dev. 2, 24. 18. Sagasti, A., Hisamoto, N., Hyodo, J., TanakaHino, M., Matsumoto, K., and Bargmann, C.I. (2001). The CaMKII UNC-43 activates the MAPKKK NSY-1 to execute a lateral signaling
decision required for asymmetric olfactory neuron fates. Cell 105, 221–232. 19. Hobert, O. (2006). Architecture of a microRNA-controlled gene regulatory network that diversifies neuronal cell fates. Cold Spring Harb. Symp. Quant. Biol. 71, 181–188. 20. Didiano, D., Cochella, L., Tursun, B., and Hobert, O. (2010). Neuron-type specific regulation of a 3’UTR through redundant and combinatorially acting cis-regulatory elements. RNA 16, 349–363.
Visual Neuroscience: A Binocular Advantage for Word Processing during Reading A recent study using a novel saccade-contingent display-change technique to control the presentation of text to each eye shows a binocular advantage for both foveal and parafoveal processing of words during natural reading. Kevin Paterson Being able to read is crucial for functioning effectively in everyday life. Most individuals read binocularly; consequently, for the vast majority of individuals, normal reading requires the precisely coordinated rotation of the two eyes so that the eyes make conjugate saccadic movements along lines of text. These saccades tend to be relatively short, lasting approximately 20–30 ms and spanning about 7–9 letters, roughly 2 of visual angle, when silently reading in alphabetic languages like English [1–3]. Each eye movement ends in a brief fixational pause (averaging 250–300 ms), during which both eyes acquire visual information that is used rapidly to establish the identity of individual words in the text. Variability in the length of these fixational pauses reflects the ease with which words can be identified, and words that are more familiar to the reader typically will receive shorter fixations. The length of the fixational pauses is therefore sensitive to cognitive processes that underlie the real-time recognition of words during reading. The superiority of binocular over monocular viewing has been demonstrated in a range of non-reading tasks, and this binocular advantage is attributed to the neural summation of the visual input to each eye [4,5]. However, the importance of binocular viewing for reading has largely been overlooked;
indeed, it is only very recently that researchers have examined the role of the two eyes in reading, focusing on the efficiency with which the oculomotor system coordinates saccadic eye movements [6–8]. This research has shown that locations of the two eyes’ fixations are generally well-coordinated and that the average disparity in these locations is less than the span of two character spaces for skilled adult readers, although on rare occasions the eyes fixate locations that are much further apart, sometimes even on different words in a sentence. There are, however, indications of a binocular advantage in reading from research showing that the coordination of the two eyes differs during binocular compared to monocular reading and that fixational pauses are shorter during binocular reading [9]. As they report in this issue of Current Biology, Jainta et al. [10] addressed this issue more fully using a novel saccade-contingent displaychange technique in which the presentation of text was either monocular or binocular throughout reading, or precisely controlled using high-speed shutter glasses so that the presentation changed from binocular to monocular (or vice versa) in real-time, triggered by the reader making a saccade that crossed an invisible boundary in the text. Participants were unaware of this change but, as I will explain in more detail below, the duration of
1Anatomy
and Developmental Biology Program, Institute of Biomedical Sciences, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile. 2Biomedical Neuroscience Institute, Santiago 8380453, Chile. *E-mail: [email protected] http://dx.doi.org/10.1016/j.cub.2014.01.031
fixational pauses on a designated target word in each sentence showed that the usual advantage for more familiar words was obtained during binocular, but not monocular, presentations. This led Jainta et al. [10] to conclude that denial of a unified visual signal derived from binocular inputs disrupts the lexical processing of words and thereby impairs the normal efficiency of reading. A central concern for eye movement research has been to establish what eye movements can reveal about the underlying cognitive processes in reading. A substantial body of evidence ([11,12], for reviews, see [1,2]), supported by computational models of eye movement control during reading [13–15], shows that the duration of fixational pauses on words is sensitive to the ease with which words can be identified. The familiarity of a word to the reader is of particular importance to this process. Indeed, a fundamental assumption of the E-Z Reader model [14,15] is that the decision about when to move the eyes during reading is governed by a process that establishes whether a word is familiar and so likely to be identified imminently. A reader’s eyes usually will dwell for momentarily longer on words that have a lower frequency of usage in text and so are less familiar to the reader. This difference in the length of fixational pauses for words with a higher rather than lower frequency of usage is described as the word frequency effect and is considered to be a hallmark of lexical processing during reading [1,2]. Disruption to the word frequency effect is associated with impairment to the normal process of word identification, and typically is observed when the visual quality of text is degraded [16–18]. For this reason, Jainta et al. [10] used the word frequency effect as a diagnostic of the efficiency of processing word identity during
