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

ABSTRACT 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.

1 Follower
11 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "Phosphorylation in the transactivating domain by p38 MAP kinases (MEF2A and C) (Han et al. 1997; Wu et al. 2000a) or ERK5 (MEF2A, C and D) (Kato et al. 2000) increases the transcriptional activity of MEF2, whereas both GSKβ (MEF2D) and cdk5- mediated phosphorylation (MEF2A, C and D) reduce MEF2- dependent transcription (Gong et al. 2003; Wang et al. 2009). Notably, phosphorylation at Ser408/444 of MEF2A/D by cdk5 inhibits MEF2 transcriptional activity in HEK-293T cells (Pulipparacharuvil et al. 2008) and cultured neurons (Gong et al. 2003) and pMEF2 has been used as a marker for reduced MEF2 activity in the brain (discussed below). Also, cdk5 phosphorylation promotes sumoylation of MEF2 in vitro (Lys403/439, MEF2A/D) (Gregoire et al. 2006; Shalizi et al. 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the brain, transcription factors are critical for linking external stimuli to protein production, enabling neurons and neuronal networks to adapt to the ever-changing landscape (Korzus 2003). Gene transcription and protein synthesis are also vital for the formation of long-term memory (Davis & Squire 1984; Hernandez & Abel 2008). Members of the myocyte enhancer factor-2 (MEF2) family of transcription factors have a well-characterized role in the development of a variety of tissues, but their role in the adult brain is only beginning to be understood. Recent evidence indicates that MEF2 regulates the structural and synaptic plasticity underlying memory formation. In stark contrast to most other transcription factors implicated in memory, however, MEF2-mediated transcription constrains (rather than promotes) memory formation. Here we review recent data examining the role of MEF2 in adult memory formation in rodents.
    Genes Brain and Behavior 06/2013; 13(1). DOI:10.1111/gbb.12058 · 3.66 Impact Factor
Show more


11 Reads
Available from