Role of miRNAs and epigenetics in neural stem cell fate determination.

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Role of miRNAs and epigenetics in neural stem cell fate determination a

Miguel Alejandro Lopez-Ramirez & Stefania Nicoli

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Yale Cardiovascular Research Center; Section of Cardiovascular Medicine; Yale University School of Medicine; New Haven, CT USA Published online: 16 Dec 2013.

Click for updates To cite this article: Miguel Alejandro Lopez-Ramirez & Stefania Nicoli (2014) Role of miRNAs and epigenetics in neural stem cell fate determination, Epigenetics, 9:1, 90-100, DOI: 10.4161/epi.27536 To link to this article: http://dx.doi.org/10.4161/epi.27536

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Epigenetics 9:1, 90–100; January 2014; © 2014 Landes Bioscience

Role of miRNAs and epigenetics in neural stem cell fate determination Miguel Alejandro Lopez-Ramirez and Stefania Nicoli* Yale Cardiovascular Research Center; Section of Cardiovascular Medicine; Yale University School of Medicine; New Haven, CT USA

Abbreviations: miRNAs, microRNA; CNS, central nervous system; NSC, neural stem cells; 3′UTR, 3′-untranslated region; primiRNA, primary miRNA; DGCR8, DiGeorge syndrome critical region 8, pre-miRNA, precursor miRNA; NE, neuroepithelial; VZ, ventricular zone; SVZ, subventricular zone; SGZ, subgranular zone; RMS, rostral migratory stream; HATs, histone acetyltransferases; HDACs, histone deacetylases; RE1, repressor element-1; REST, RE1 silencing transcription factor; CoREST, C-terminal cofactor for REST; H3K4, histone H3 methylation at lysine 4; Ezh2, enhancer of Zeste homolog 2; LSD1, lysinespecific demethylase A1; DNMT, DNA methyltransferases; MBD, methyl-CpG binding domain; MeCP2, methyl-CpG binding protein 2; MBD1, methyl-CpG binding protein 1; SWI/SNF, switch/sucrose non-fermenting; ISWI, imitation switch; CHD, chromo helicase DNA binding; INO80, inositol auxotroph 80; BAFs, Brg/Brm-associated factors

The regulation of gene expression that determines stem cell fate determination is tightly controlled by both epigenetic and posttranscriptional mechanisms. Indeed, small noncoding RNAs such as microRNAs (miRNAs) are able to regulate neural stem cell fate by targeting chromatin-remodeling pathways. Here, we aim to summarize the latest findings regarding the feedback network of epigenetics and miRNAs during embryonic and adult neurogenesis.

Introduction The cell diversity and high degree of complexity that constitute the developing and adult central nervous system (CNS) are generated by neural stem cells (NSCs). NSCs are subject to neural lineage specification due to changes in gene expression pattern in response to cell-intrinsic mechanisms and cell-extrinsic molecular cues.1,2 Recent studies have shown that epigenetics play an important role in determining the gene expression program of NSCs. Indeed, neural epigenetic control implies heritable changes in gene expression that do not alter the genomic sequence including, histone modifications, DNA methylation, chromatin remodeling and transcriptional feedback loops.2 The epigenetic machinery mediates the switch in the state of chromatin structure and not only provides a platform to recruit binding proteins to allow transcriptional activation or repression, but also confers “bivalent chromatin domains” poised for gene activation.1,3,4 More recently, non-coding RNAs, such as microRNAs (miRNAs), have been included in the epigenetics list, and have been shown to work in concert with the epigenetic machinery in order to regulate NSC fate progression to differentiated progeny.5,6 miRNAs *Correspondence to: Stefania Nicoli; Email: [email protected] Submitted: 10/14/2013; Revised: 12/06/2013; Accepted: 12/16/2013; Published Online: 12/16/2013; http://dx.doi.org/10.4161/epi.27536

are phylogenetically conserved small non-coding RNAs (~22 nt long), and their control of gene expression occurs at the posttranscriptional level by translation inhibition, mRNA decay, or both via specific sequence interactions with the 3′ untranslated region (3′UTR) of the target genes.7,8 miRNA synthesis and maturation follows a stepwise process that is compartmentalized between the nucleus and the cytoplasm. In the nucleus, the primary miRNA transcript (pri-miRNA) is transcribed by RNA polymerase II, resulting in a transcript with a stem-loop structure of approximately 70 nucleotides, a 5′ 7-methylguanylate cap and a 3′-polyadenylated tail.9,10 Drosha, a ribonucleoprotein RNase III enzyme,11 and its cofactor DiGeorge syndrome critical region 8 (DGCR8), a double-stranded RNA binding protein, mediate the release of the stem-loop intermediate known as the precursor miRNA (pre-miRNA).12 The nascent pre-miRNA is then shuttled from the nucleus to the cytoplasm via exportin-5.13 In the cytoplasm, the terminal loop is cleaved from the premiRNA by Dicer, another ribonucleoprotein RNase III enzyme that was first discovered due to its role in processing small interfering RNAs.7 High throughput sequencing experiments have suggested that NSCs possess a specific repertory of miRNAs to modulate their differentiation.14-16 In this review, we will focus on the cellular and molecular mechanisms that miRNAs and the epigenetics machinery coordinate in order to regulate signaling networks during embryonic and adult NSC maintenance and differentiation.

Embryonic and Adult Neurogenesis The mammalian CNS developmental program begins at the neural plate and neural tube, when the neuroepithelial (NE) cells form a continuous layer of cells with apical-basal polarity.17 NE cells are considered the earliest form of NSC, with the potential to give rise to the diversity of neurons and glia cells during development.18,19 At the onset of neurogenesis, NE cells increase the pool of stem cells by undergoing an amplification phase and a fraction of NE cells shift from proliferation to

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Keywords: microRNAs, epigenetics machinery, neural stem cells, neurogenesis, cell fate determination

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neuron-generating divisions.17,20 In addition, NE cells also give rise to the second type of NSCs, the radial-glia cells, recognized as the major neural progenitor population (Fig. 1).18,21-23 Similar to NE cells, radial-glia cells express the intermediate filament protein nestin, maintain an apical-basal polarity, undergo interkinetic nuclear migration (movement of the nucleus during cell cycle) and their densely packed cell bodies line the apical surface of the pseudostratified ventricular zone (VZ).21-24 However, radial-glia cells show distinctive features that include the expression of several astroglial markers, loss of epithelial tight-junction proteins at the cell-cell junction and show a characteristic cell morphology, in which a long basal process maintains contact with the pial surface while a shorter apical process projects toward the lumen of the VZ (Fig. 1).17,22 Initially, the radialglia basal process serves as a scaffold for the newly born neurons emerging from the VZ in order to migrate toward the cortical plate. Concomitantly radial-glial cells produce intermediate progenitors also known as transit-amplifying cells (Fig. 1).20,24,25 Studies using video time-lapse microscopy in GFP knock-in transgenic mice specific for neurogenic progenitor cells (a type of transit-amplifying cells) revealed that the major sources of neuron-generating cells occurs in the subventricular zone (SVZ) via multiple rounds of cell divisions before the fate switches to terminally differentiated neurons (Fig. 1).20 Moreover, the switch from neurogenesis to gliogenesis occurs in the early neonatal stage.26 Oligodendrocytes are derived from oligodendrocytic progenitor cells produced during early developmental stages, and the radial-glia cells lose their ventricular localization by migration toward the cortical plate where they acquire the multipolar morphology of differentiated astrocyte.21 Adult mammalian neurogenesis retains several of the cellular and molecular processes of neuronal development in embryonic stages (Fig. 1).27,28 However, it is well known that the adult mammalian brain maintains only two neurogenic niches: the SVZ of the lateral ventricles and the subgranular zone (SGZ) in the dentate gyrus of the hippocampus.29,30 The NSCs located in the SVZ (named type B cells) extend basal processes that interact with the brain vasculature to support the adult neurogenic niche.31 Type B cells give origin to the transit-amplifying progenitors (termed type C cells), which proliferate to generate the committed neuroblasts (type A cells) that migrate along the rostral migratory stream (RMS) to reach the olfactory bulb where they differentiate into interneurons (Fig. 1).22,32 In addition, it has also been reported that SVZ type B cells give rise to oligodendrocytes in normal and injured adult brain.33,34 In the neurogenic niche of the SGZ, NSCs (named type 1 cells) present radial glia-like characteristics and give origin to a nonradial precursor known as the type 2 cell, which in turn generates neuroblasts (named type 3 cells) before differentiating into hippocampal granule cells.28,30,35 In contrast to mammals, the adult brains of other animal models, such as zebrafish (Danio rerio), show 16 neurogenic niches distributed all along the rostro-caudal adult brain axis.36 These extensive neurogenic areas confer to the zebrafish brain the ability to fully regenerate after severe traumatic brain lesion.37

Cellular Mechanism of Neural Cell Fate Determination Early studies of neural fate specification in Caenorhabditis elegans and Drosophila melanogaster indicated that cell division patterns play important roles in neural cell fate determination and generation of cell diversity.38,39 Indeed, studies using lineage tracing in mammalian cerebral cortices have shown that both NE cells and radial-glial cells first increase their number by undergoing symmetric proliferative divisions. This mean that one NE cell begets two NE cells or one radial-glia cell gives rise to two radial glia cells.18,40,41 As development proceeds, sequential fate restrictions take place via symmetric42,43 and asymmetric cell divisions in the VZ and SVZ.44 Chenn and McConnell, suggested that the symmetric and asymmetric cell divisions were associated with the cleavage orientation of progenitor cells.45 For instance, cleavage along the vertical plane of the neural progenitors would be more likely to result in two daughter cells that inherit apical cell fate determinants and remain in the VZ to continue cell proliferation (symmetric cell division). Whereas cleavage along the horizontal plane of neural progenitors generate asymmetric cell division that result in apical and basal daughter cells.45 The latter migrates out of the VZ and differentiates into a neuron whereas the former (apical daughter cells) remains attached to the apical VZ.45 Another cellular mechanism that determines the total number of neurons and cell fate determination during neurogenesis is cell cycle regulation.46 Mathematical modeling suggests that a 50% increase in the rate of cell cycle progression in neural progenitors doubles the neuron number during neurogenesis.46,47 In agreement with this observation, neocortical areas show differential regulation of cell cycle kinetics of progenitors that give rise to a different number of neurons that define the anatomical organization and cytoarchitecture of the embryonic cortex.47 Furthermore, cell cycle regulators influence cell fate determination. An increase in the length of the cell cycle leads to a premature switch of NE cells from proliferative to neuron-generating divisions that result in premature neurogenesis in developing mouse embryos.48 It was suggested that lengthening the G1 phase of the NE cell cycle is sufficient to trigger neurogenesis, because even if there is an unequal distribution of determining factors upon mitosis, the cell cycle will be too short, resulting in symmetric daughter cell fates. But, if the cell cycle is long enough, the determining factors are able to induce differentiation resulting in neuron-generating divisions.46,48

Epigenetics Machinery and microRNAs: Molecular Regulators of Neural Cell Fate Program Epigenetics A defining feature of NSCs is their ability to maintain the stem cell population by undergoing self-renewal, and the generation of different neural cells by their multipotent capacity (Fig. 1). Epigenetic mechanisms of gene regulation play a crucial role in these two characteristics. First, the heritable epigenetic code implies establishing a specific chromatin state characterized by specific patterning of histone modifications, which have been

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Figure 1. Schematic illustration of miRNAs function in neuronal fate determination during embryonic and adult neurogenesis. Neuroepithelial cells give origin to radial glia, which in turn undergo self-renew via symmetric (not shown) and asymmetric cell divisions (black arrows) in order to amplify the pool of NSCs during embryonic neurogenesis. A variety of neurons are originated from NSCs and intermediate progenitors via sequential fate restrictions regulated by crosstalk between miRNAs, signaling pathways and the epigenetic machinery as indicated by squares. Some radial glia cells are converted into astrocytic stem cells (B cell). B cells give origin to neuronal progenitors (C cell), which are the direct progeny of committed neuroblast (A cell) that differentiate into mature neuron. miRNAs associated with regulation of NSCs maintenance and neuronal commitment are shown in circles. Colored arrows indicate whether the cellular response is increased (↑) or decreased (↓).


timing and reduction of neuronal output (Fig. 2).64 Furthermore, mouse embryonic neural progenitors present “bivalent domains” characterized by high levels of both H3K27 trimethylated (H3K27me3) and H3K4me3 at key neurogenic genes. These chromatin domains are silenced but ready to be expressed upon the specific molecular cues.65 Indeed, recruitment of H3K27me3 demethylase activity at the specific loci is essential for bivalent domain resolution during neurogenesis (Fig. 2).65 Another histone demethylase with important roles in regulating NSC proliferations is the lysine-specific demethylase A1 (LSD1),66 which specifically resolves mono- or di-methylation of H3K4 in order to induce gene silencing (Fig. 2).67 DNA methylation DNA methylation occurs at the cytosine residue in CpG dinucleotides and is associated with transcriptional repression. Members of the DNA methyltransferases family (DNMT1, -3a and -3b) establish DNA methylation patterns in the genome during embryogenesis.53,68 Additionally, the DNA methylation pattern can be inherited during symmetric cell divisions in order to maintain the chromatin state that regulates gene expression (Fig. 2). Indeed, methylation of CpG-rich (CpG islands) promoters is recognized as a hallmark of gene repression that facilitates lineage restriction by preventing transcriptional initiation and/ or stabilizing gene silencing.52,68 For example, at the onset of neurogenesis, embryonic NSCs are unable to give rise to macroglia cells, astrocytes and oligodendrocytes, due to DNA hypermethylation at the promoter regions of many astrocyte-specific genes driven by JAK-STAT signaling.69,70 As development proceeds, the promoter regions become demethylated conferring potential to NSCs to differentiate into macroglia cells in response to glia-inducing stimuli.71 In addition, methylated regions are also regulated by the transcriptional repressors methyl-CpG binding domain (MBD) proteins including methyl-CpG binding protein 2 (MeCP2) and methyl-CpG binding protein 1 (MBD1) that recognized methylated CpG sequences (Fig. 2). Mutations of MeCP2 have been associated with the sporadic mental retardation disorder Rett syndrome due to loss of appropriate epigenetic control during neuronal development.72 Moreover, MBD1 is a transcriptional repressor of fibroblast growth factor 2 (Fgf-2),73 and loss of function of MBD1 in mice selectively affects neuronal differentiation and genomic stability, suggesting that DNA methylation might play important roles in genomic stability in the CNS (Fig. 2).73,74 Chromatin remodeling Gene expression is also regulated by the ATP-dependent chromatin remodeling complexes by altering DNA accessibility to transcription factors and to chromatin modifying proteins.75 The ATPase activity of this family of protein complexes is associated with disruption of nucleosome-DNA contacts, movement of nucleosome along DNA and/or exchanges of nucleosomes in order to regulate transcriptional activation and repression (Fig. 2).76-78 The family of ATP-dependent chromatin remodelers is grouped into four types, based on the sequence homology in their ATPase domains: switch/sucrose non-fermenting (SWI/ SNF), imitation switch (ISWI), chromo helicase DNA binding (CHD) and inositol auxotroph 80 (INO80).52 The mammalian




shown to specify gene expression patterns, without changes in the DNA sequence, associated with the mechanism of cellular memory in order to maintain the poised nature of NSCs.4,49 Moreover, in early neurogenesis the multipotency of NSC is reduced over time due to changes in the gene expression program associated with specification of neural cell lineages (Fig. 1). Indeed, genes transcribed in earlier progenitors are gradually silenced whereas subsets of cell type-specific genes are turned on, mediated in part by the epigenetic machinery as discussed below (Fig. 2).4 Histone modifications The basic unit of the eukaryotic chromatin is the nucleosome core particle, consisting of superhelical turns of DNA wrapped around an octamer of the core histone proteins (formed by 2 copies of individual histones, H2A, H2B, H3, and H4).50 Histones are subject to posttranslational modification at the N- and C-terminal tails (Fig. 2).51 A series of recent studies have shown that histone acetylation and methylation constitute important molecular mechanisms that regulate gene expression in neural cells.52,53 Histone acetylation is regulated by two groups of enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs promote lysine acetylation at the ε-amino group (NH3 +) that results in removal of the positive charge, thereby relaxing chromatin condensation that is associated with active gene transcription.51,54 Moreover, histone acetylation is a reversible process mediated by HDACs. Histone deacetylation, mediated by HDACs, is linked to transcriptional repression due to an increase in chromatin compaction.50,51 For instance, NSC self-renewal is in part regulated by the transcription factor TLX by directly recruiting HDACs to its downstream target genes, such as the cyclin-dependent kinase inhibitor, p21, and the tumor suppressor gene, PTEN, resulting in the positive regulation of cell cycle progression (Fig. 2).55 Another example of HDAC recruitment in neurogenesis is illustrated by the transcriptional repressor element-1 (RE1) silencing transcription factor (REST), also known as neuron-restrictive silencer factor (NRSF).56,57 In pluripotent stem cells and NSC, REST silences neuronal genes by orchestrating epigenetic mechanism.58,59 Indeed, REST interacts with the RE1 element of target genes and recruits C-terminal cofactor for REST (CoREST) and mSin3A in order to form a co-repressor platforms that recruit HDAC1/2 and histone methyltransferases, which causes chromatin condensation and gene silencing (Fig. 2).60 Histone methylation is associated with transcriptional activation and repression, as well as with bivalent chromatin domains (Fig. 2).51,54,61,62 Indeed, the difference in the functional outcome depends on several factors including the type of histone, and the location and number of methyl groups at the lysine and arginine residue. For instance, histone H3 methylation at lysine 4 (H3K4), H3K36, and H3K79 are linked to gene activation, whereas H3K9 and H3K27, as well as H4K20 and H4K59, have been associated with gene repression.54,63 Recently, it has been reported that the enhancer of Zeste homolog 2 (Ezh2), a H3K27 methyltransferase and component of the polycomb group protein complex, is associated with modulation of NSC cell fate in the cerebral cortex.64 Loss of Ezh2 in progenitor cells results in a marked upregulation of gene expression, changes in the developmental




Figure 2. Molecular mechanisms of the epigenetic-miRNAs regulatory network associated with chromatin remodeling during neurogenesis. (A) Histone modifications are mediated by acetylation, deacetylation and methylation. HATs relax chromatin structure and facilitate transcription, while HDACs increase chromatin condensation and repress transcription. miR-9 and let-7 regulate the expression of the transcription factor TLX that directly recruits HDACs in order to mediate p21 and Pten gene repression in NSCs. miR-137 has emerged as an important regulator of histone methylation regulatory pathway by targeting the demethylase, LSD1, and the H3K27 methyltransferase, Ezh2. miR-137-Ezh2 network might be associated in balancing genespecific bivalent domains in NSCs. 2 (B) DNA methylation is associated with transcriptional repression and negative regulation of several brain-enriched miRNAs. The transcriptional repressor MBD protein, MeCP2, binds to methylated genes in order to silence genes. MeCP2 has been identified as a target of miR-132 in neurons. The transcription factor REST regulates the expression of brain-enriched miR-9/9* and miR-124. miR-9/9* act as a negative feedback regulatory loop on REST silencing complex. (C) ATP-dependent chromatin remodeling complex alter the chromatin structure in order to regulate NSC fate determination. BAF53a expression levels are regulated by miR-124 and miR-9* during the transition between NSCs proliferation to differentiated post-mitotic neuron.122

Crosstalk between Brain-Enriched miRNAs and the Epigenetic Machinery miR-9 miR-9/9* is a highly conserved miRNA abundantly expressed in the CNS of vertebrates.92,93 miR-9 is expressed in neurogenic regions and delimits the midbrain-hindbrain boundary in embryonic vertebrate models, such as Xenopus and zebrafish, by targeting hairy1, her5, her9 and several components of the FGF signaling (fgf8, fgfr1 and canopy1).94,95 Furthermore, miR-9 is expressed in NSCs, neuronal progenitors and some post-mitotic

neurons to dictate pleotropic responses (Fig. 1).95-97 In human neural progenitor cells inhibition of endogenous miR-9 reduces proliferation and promotes cell migration without consequences in neuronal differentiation.96 In contrast, miR-9 decreases TLX, a self-renewal regulator, in adult mouse NSCs that results in negative modulation of proliferation and positive effects on neural cell differentiation.98 Furthermore, gain and loss of function analysis of miR-9 during development of mouse and zebrafish embryos showed that miR-9 suppresses neural progenitor proliferation and promotes neuronal differentiation by modulation of several target genes including Foxg1, Nr2e1, Meis2, and Gsh2.86,94,99 In Drosophila, miR-9a loss and gain of function studies have demonstrated that miR-9a plays important roles in regulating the number of sensory organ precursors (SOPs) by inhibiting the neuronal cell fate in non-SOP cells via silencing of senseless target gene.100 More recently, it has been appreciated that miR-9 is a component of ultradian oscillations that mediate transition from neural proliferative divisions to neural differentiation by dampening Hes1 ultradian oscillations in neural progenitors.101 Furthermore, miR-9 has been suggested to control the ambivalent state of neural progenitors by directly targeting a set of antagonistic genes associated with progenitor proliferation, zic5 and her6, and neuronal differentiation, elavl3.97 All these studies showed that miR-9 acts as a neural regulatory switch at different developmental stages by regulating multiple targets differentially expressed in both spatiotemporal and cellular context-dependent manners.102 Moreover, chromatin immunoprecipitation analysis revealed that REST acts as a regulator of miR-9 genes (Fig. 2).103,104 Indeed, REST inhibits miR-9-2 promoter activity in undifferentiated neuroblastoma cell-line.104 Interestingly, miR-9 and miR-9* (miRNA with similarly sized as miR-9 synthesized from the opposite strand) have a negative feedback loop on REST silencing complex by silencing REST itself and CoREST gene during neural differentiation.104,105 In addition, hypermethylation of CpG islands in the miR-9 gene loci have been associated with various types of cancers indicating the profound control of miRNA expression by epigenetic mechanisms (Fig. 2).6 miR-34a Another miRNA with roles in neuronal fate determination of NSCs is miR-34a. miR-34a is an intergenic miRNA whose promoter harbors CpG islands silenced by hypermethylation in numerous types of cancer (Fig. 2).106 Recently, it was reported that levels of miR-34a expression are under the control of TAp73, a member of the p53 family, which in turn regulates neuronal differentiation via SIRT1 downregulation.107,108 However, miR-34a has also been observed to have negative roles in neuronal differentiation by targeting of Numbl and concomitant increase in Notch signaling (Fig. 1).109 miR-124 miR-124 is temporally upregulated during neural development110,111 and adult neurogenesis.112 Indeed, the expression of miR-124 is very low in neural progenitors but is highly expressed in neuroblast and mature neurons112-114 (Fig. 1). miR-124 has the ability to instruct non-neural cells, such as HeLa cells, to acquire neural gene programs.115 In addition, fibroblast cells transfected with miR-124 alone or in combination with miR-9/9* acquired




genome contains 29 members of the SWI2/SNF2-like ATPase family, and two of these, Brg and Brahma (Brm), form part of a chromatin remodeling complex with 10 core subunits BAFs (Brg/ Brm-associated factors).79 Recently, it was shown that the transition from proliferative NSC to differentiated neuron involved switch in subunit composition of npBAF complex. NSC in proliferation requires Brg/Brm-associated factor containing BAF54a and BAF53a subunits, whereas as neural progenitors exit cell cycle the subunits are replaced by the alternative BAF45b, BAF45c and BAF53b subunits in order to establish a post-mitotic neurons (Fig. 2).79 MicroRNAs A number of recent studies have demonstrated the essential role of miRNAs in regulating cellular mechanisms of NSC maintenance and neural commitment (Fig. 1).8,80,81 In addition, miRNAs might also influence the heterogeneity among NSC in the vertebrate nervous system43 by facilitating their transition into new gene expression programs that control their developmental potential and responsiveness to environmental signals. It has been proposed that the cellular miRNA milieu might also be unique in each cell type generated by NSCs and be required to facilitate developmental transitions during neurogenesis and gliogenesis.14-16 Indeed, initial approaches showed that removal of the Dicer gene has serious consequences in the morphogenesis of the CNS in zebrafish.82 However, global Dicer mouse knockouts are lethal at early stages of development.83,84 Our knowledge of key aspects of miRNA involvement in NSC biology was achieved by conditional knockout of the enzyme Dicer and/or individual miRNAs in different neural cells throughout development.85-87 Using these approaches, cell cycle-regulating miRNAs have been identified that regulate self-renewal of neural progenitors (Fig. 1).88,89 Interestingly, experimental evidence suggests that the timing of Dicer deletion during neural development results in different phenotypes and sometimes in contradictory results. For instance, loss of Dicer in the developing mouse cortex using Emx1-Cre did not affect the neural progenitors cell cycle progression, differentiation or viability at E12.5, while defective cortical layering was observed at E13.5 and postnatally.90 In contrast, in the developing retina, loss of Dicer function appears to increase the number of early generated cell types (ganglion cells) and decrease in the production of late-born cells types (rods and Müller cells).91 These differences have been related to the incomplete deletion of Dicer or gradual decay of miRNAs due to differential miRNA stability in these conditional knockouts.

proliferation, whereas endogenous inhibition of miR-137 increases neuronal differentiation in mouse forebrain.1 Additionally, miR137 might have roles in regulating the poised state of adult NSC due to its ability to target Ezh2 (Fig. 2).135 miR-184 miR-184 expression in NSCs is regulated at the epigenetic level by the methyl-CpG binding protein, MBD1.136 Increased levels of miR-184 promote NSC proliferation and inhibit neural lineage progression by targeting Numbl, while the expression of MBD1 represses miR-184 to allow the differentiation of NSC (Fig. 2).136 let-7 let-7 was the first miRNA identified in a wide range of species and tissues including the brain.137 Although the number of let-7 genes varies between organisms138 their mature form is broadly conserved between species.139 Furthermore, members of the let-7 family differ at the 3′ region that might play a role in compensatory target recognition and/or selectivity.140 For instance, let-7i has been shown to inhibit neuronal differentiation by targeting MASH1 and NGN1, two proneural genes,141 while let-7b targets TLX and cyclin D1 that result in reduced progenitor proliferation and increased neuronal differentiation (Fig. 1).142 Recently, let-7c has been reported to be involved in the chronological neurogenesis in Drosophila. Indeed, the cell fate of late-born neurons is regulated by endocrine stimuli that induce the spatial distribution of let-7 expression. The let-7 target gene Abrupt, a transcription factor, modulates the expression levels of the cell adhesion molecule Fasciclin II that plays important roles in neuronal cell identity.143 The diversity in function among let-7 family members has also been observed in different types of cancer cells, where their expression has been found to be under the control of members of DNA methyltransferases by promoting DNA hypermethylation in the promoter region (Fig. 2).6

Conclusions A great effort has been made within the past few years to uncover the gene regulatory network established by chromatin remodeling proteins (epigenetic machinery) and miRNAs during neurogenesis. Indeed, neurogenesis is a process under tight balance and spatio-temporal regulation of gene expression throughout the entire animal’s life. The interplay between epigenetic machinery and miRNAs result in fine-tuning of multiple mRNA transcripts associated with several cellular mechanism of NSCs fate determination, including cell cycle, cell patterning and their role in symmetric and asymmetric cell divisions remains to be fully elucidated. An interesting prospective for the future of these fields will be to uncover whether miRNAs and epigenetics signaling overlap during neuronal cell death such as in aging processes or Alzheimer disease where, both aberrant DNA methylation and miRNAs expression has been observed but not correlated yet. Understanding the epigenetic-miRNA regulatory network might reveal potential therapeutic targets to treat diseases that affect the CNS. Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.




a neuron phenotype, suggesting that the combination of these brain-enriched miRNAs have instructive roles in neural fate determination by targeting several pathways.116,117 For example, miR-124 targets the mRNA of PTBP1, a global repressor of alternative splicing,118 laminin γ1 and integrin β1119 in progenitor cells in order to induced neuronal differentiation. Consistent with the role of miR-124 in promoting neuronal differentiation, neural cells missing endogenous miR-124 have increased expression of nonneural genes and loss of neuronal properties.103 Therefore neuronal tissues require high levels of miR-124 in vivo. One of the genes targeted in this process is SCP1, a phosphatase with anti-neural activity.120 In the adult brain, miR-124 induces constitutive and acute neurogenesis by repression of Sox-9112 and by targeting Jag1, one of the major Notch ligands in neurogenic progenitors located in the SVZ.121 Interestingly, similarly to miR-9, miR-124 coordinates and regulates signaling networks and chromatin remodeling to induce neuronal phenotypes. Recently, Yoo and colleagues122 demonstrate that miR-124 in combination with miR-9* regulate the chromatin-remodeling mechanism associated with the switch from neural progenitor proliferation to neuron-generating divisions. Moreover, absence of REST during neuron-generating divisions allows the expression of miR-124 and miR-9*, which in turn represses BAF53a, an ATP-dependent chromatin remodeling protein, in order to promote dendritic outgrowth (Fig. 2).122 miR-132 miR-132 has been shown to play important roles in dendrite maturation and function of newborn neurons in the adult hippocampus.123-125 Mechanistically, miR-132 is rapidly induced by BDNF in order to regulate dendritic morphogenesis by targeting a Rho GTPase protein, p250GAP (Fig. 1).126,127 In addition, MeCP2, an important methyl-CpG binding protein with roles in neuronal maturation, has been identified as a target of miR-132 (Fig. 2).128 Altered expression levels of MeCP2 affect dendritic development and synaptogenesis resulting in neurodevelopmental defects. It has been proposed that MeCP2 expression in neurons is controlled by a feedback loop by which MeCP2 increases BDNF levels that subsequently increases the expression levels of pre-miR-132 (Fig. 2).127 miR-137 miR-137 is expressed in both embryonic and adult vertebrate brains15,129-131 and is found to be enriched in synaptosomes isolated from rat forebrains.132 In vitro, miR-137 levels increase gradually during differentiation of adult NSCs.131,133 It has been suggested that miR-137 induces differentiation of adult mouse NSCs by negative modulation of cell cycle regulation via direct silencing of CDK6 expression (Fig. 1).133 In addition, miR-137 has the capacity to facilitate the transition from embryonic stem cells toward the neuronal fate by targeting transcription factors, KLF4 and TBX3.134 miR-137 forms a regulatory loop with the histone demethylase, LSD1, and the transcription factor, TLX, in order to regulate NSC fate determination.130 Indeed, TLX represses miR-137 expression through the recruitment of LSD1 in NSCs that in turn maintain cell proliferation. Interesting, miR-137 can also inhibit LSD1 expression resulting in decreased NSC proliferation and premature neural differentiation in embryonic mouse brains (Fig. 2).130 Overexpression of miR-137 promotes NSC

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The authors are grateful to Anand Narayanan, Catherine Hare, Guillermina Hill-Teran, Emma Ristori and Corey Smith for their critical reading of this manuscript.

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