Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo

Center for Neuroscience, Aging, and Stem Cell Research, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2008; 105(27):9397-402. DOI: 10.1073/pnas.0802876105
Source: PubMed


Emerging evidence suggests that myocyte enhancer factor 2 (MEF2) transcription factors act as effectors of neurogenesis in the brain, with MEF2C the predominant isoform in developing cerebrocortex. Here, we show that conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size. NSC proliferation and survival were not affected. Conditional null mice surviving to adulthood manifested more immature electrophysiological network properties and severe behavioral deficits reminiscent of Rett syndrome, an autism-related disorder. Our data support a crucial role for MEF2C in programming early neuronal differentiation and proper distribution within the layers of the neocortex.

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    • "Notably, the top four most enriched hexamers contain one or more UGC triplets (Figures 2F and S2F), and two of the hexamers matched those detected by the PEAKS analysis (compare Figures 2F and 2A). We generated a merged in vivo binding map (Licatalosi et al., 2008) displaying the mean, normalized distributions of nSR100 293T cell PARiCLIP crosslink sites within 400 nt windows surrounding the 157 conserved target exons, and a set of $400 control exons that are not nSR100 targets but that have a comparable PSI distribution . We observed a strong enrichment for nSR100 binding to intronic sequences proximal to the 3 0 splice sites of target exons relative to control exons, with a pronounced peak approximately À15 nucleotides from the 3 0 splice site (Figures 3A and S3A). "
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    ABSTRACT: The vertebrate and neural-specific Ser/Arg (SR)-related protein nSR100/SRRM4 regulates an extensive program of alternative splicing with critical roles in nervous system development. However, the mechanism by which nSR100 controls its target exons is poorly understood. We demonstrate that nSR100-dependent neural exons are associated with a unique configuration of intronic cis-elements that promote rapid switch-like regulation during neurogenesis. A key feature of this configuration is the insertion of specialized intronic enhancers between polypyrimidine tracts and acceptor sites that bind nSR100 to potently activate exon inclusion in neural cells while weakening 3' splice site recognition and contributing to exon skipping in nonneural cells. nSR100 further operates by forming multiple interactions with early spliceosome components bound proximal to 3' splice sites. These multifaceted interactions achieve dominance over neural exon silencing mediated by the splicing regulator PTBP1. The results thus illuminate a widespread mechanism by which a critical neural exon network is activated during neurogenesis.
    Molecular Cell 09/2014; 56(1). DOI:10.1016/j.molcel.2014.08.011 · 14.02 Impact Factor
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    • "We observed a significant decrease in NeuN/BrdU double-positive cells and a significant increase of S100b/BrdU double-labeled cells (Figure 5D). Together, these data indicate that MEF2A plays an important role in adult hippocampal neurogenesis, both in vitro and in vivo, akin to the role of this family of transcription factors we previously demonstrated during embryonic neurogenesis in the developing cerebrocortex (Li et al., 2008). "
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    ABSTRACT: Redox-mediated posttranslational modifications represent a molecular switch that controls major mechanisms of cell function. Nitric oxide (NO) can mediate redox reactions via S-nitrosylation, representing transfer of an NO group to a critical protein thiol. NO is known to modulate neurogenesis and neuronal survival in various brain regions in disparate neurodegenerative conditions. However, a unifying molecular mechanism linking these phenomena remains unknown. Here, we report that S-nitrosylation of myocyte enhancer factor 2 (MEF2) transcription factors acts as a redox switch to inhibit both neurogenesis and neuronal survival. Structure-based analysis reveals that MEF2 dimerization creates a pocket, facilitating S-nitrosylation at an evolutionally conserved cysteine residue in the DNA binding domain. S-Nitrosylation disrupts MEF2-DNA binding and transcriptional activity, leading to impaired neurogenesis and survival in vitro and in vivo. Our data define a molecular switch whereby redox-mediated posttranslational modification controls both neurogenesis and neurodegeneration via a single transcriptional signaling cascade.
    Cell Reports 07/2014; 8(1). DOI:10.1016/j.celrep.2014.06.005 · 8.36 Impact Factor
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    • "Adding to the complexity of the Mef2 family tree, multiple splice variants have been identified for many of the paralogs [31], [33]. Despite being initially described as exclusive to differentiating muscle, members of the Mef2 family of transcription factors have been shown to be expressed in the developing brain, and have also been shown to play crucial roles in programming early neuronal differentiation and proper distribution within the layers of the neocortex [34]. In one example, Cho et al. report that forced expression of a constitutively active MEF2C increases the generation of neurons with dopaminergic properties derived from hESC-derived neural progenitor cells (NPCs) [35]. "
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    ABSTRACT: MiR-9, a neuron-specific miRNA, is an important regulator of neurogenesis. In this study we identify how miR-9 is regulated during early differentiation from a neural stem-like cell. We utilized two immortalized rat precursor clones, one committed to neurogenesis (L2.2) and another capable of producing both neurons and non-neuronal cells (L2.3), to reproducibly study early neurogenesis. Exogenous miR-9 is capable of increasing neurogenesis from L2.3 cells. Only one of three genomic loci capable of encoding miR-9 was regulated during neurogenesis and the promoter region of this locus contains sufficient functional elements to drive expression of a luciferase reporter in a developmentally regulated pattern. Furthermore, among a large number of potential regulatory sites encoded in this sequence, Mef2 stood out because of its known pro-neuronal role. Of four Mef2 paralogs, we found only Mef2C mRNA was regulated during neurogenesis. Removal of predicted Mef2 binding sites or knockdown of Mef2C expression reduced miR-9-2 promoter activity. Finally, the mRNA encoding the Mef2C binding partner HDAC4 was shown to be targeted by miR-9. Since HDAC4 protein could be co-immunoprecipitated with Mef2C protein or with genomic Mef2 binding sequences, we conclude that miR-9 regulation is mediated, at least in part, by Mef2C binding but that expressed miR-9 has the capacity to reduce inhibitory HDAC4, stabilizing its own expression in a positive feedback mechanism.
    PLoS ONE 04/2014; 9(4):e94348. DOI:10.1371/journal.pone.0094348 · 3.23 Impact Factor
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