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.

    • "Archives of Biochemistry and Biophysics to both neuronal and craniofacial deregulation, consequences of an abnormal expression of MEF2C protein. Studies with mice or zebrafish models showed similar abnormalities in the absence of MEF2C protein [9] [30] [35] [44]. "
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    ABSTRACT: MEF2C is a crucial transcription factor for cranial neural crest cells development. An abnormal expression of this protein leads to severe abnormalities in craniofacial features. Recently, a human disease (MRD20) was described as a consequence of MEF2C haploinsufficiency. These patients show severe developmental delay, intellectual disability and dysmorphic features. Zebrafish presents two MEF2C orthologues, mef2ca and mef2cb. In this study we demonstrate a highly conserved pattern of chromosome localization for MEF2C between human and zebrafish, a similar protein sequence and tissue expression profile. We have focused our functional analysis on the zebrafish orthologue mef2cb. We identified three new exons through 5' RACE and described two new transcriptional start sites (TSS). These alternative TSS reflect the occurrence of two alternative promoters differentially regulated by nuclear factors related to craniofacial or neuronal development such as Sox9b, Sox10 and Runx2. We also predict that mef2cb gene may be post transcriptionally regulated by analysing the structure of its 5' UTR region, conserved throughout evolution. Our study provides new insights in MEF2C conservation and provides the first evidence of mef2cb regulation by both transcriptional and post transcriptional mechanisms, thus contributing to validate zebrafish as a good model for future studies concerning MEF2C dependent pathologies.
    No preview · Article · Dec 2015 · Archives of Biochemistry and Biophysics
    • "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.
    No preview · Article · Sep 2014 · Molecular Cell
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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.
    Full-text · Article · Jul 2014 · Cell Reports
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