MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex.

Leifer, Dana; Krainc, Dimitri; Yu, Yie Teh; McDermott, John C.; Breitbart, Roger E.; Heng, John E.; Neve, Rachael L.; Kosofsky, Barry E.; Nadal‐Ginard, Bernardo; Lipton, Stuart A.

doi:10.1073/pnas.90.4.1546

Cited by 203 publications

(183 citation statements)

References 27 publications

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“…Normally, MEF2 activity ( Fig. S1 A) (5,6) and protein of the MEF2 isoforms (2,12) are widely distributed in specific patterns in the brain. In adult n-Cre ϩ /Mef2c loxp/⌬2 -null mutant mice, we observed a marked decrease in brain size, cortical thickness (Fig.…”

Section: Mef2c Conditional Knockout Micementioning

confidence: 99%

“…MEF2C belongs to the myocyte enhancer factor 2 (MEF2) subfamily of the MADS (MCM1-agamous-deficiens-serum response factor) gene family (2,3). We cloned MEF2C from developing mouse brain, and Eric Olson and colleagues then discovered it in the heart (2,4,5).…”

mentioning

confidence: 99%

“…In cerebrocortex, MEF2 transcriptional activity is restricted to differentiated cortical neurons in a specific laminar pattern, and its distribution increases along the rostrocaudal axis (2,4,6). These features led to speculation on the potential role of MEF2C in the architechtonics of the cerebral cortex (2). Previous studies demonstrated an important role for MEF2C in heart development (7).…”

mentioning

confidence: 99%

“…We cloned MEF2C from developing mouse brain, and Eric Olson and colleagues then discovered it in the heart (2,4,5). In cerebrocortex, MEF2 transcriptional activity is restricted to differentiated cortical neurons in a specific laminar pattern, and its distribution increases along the rostrocaudal axis (2,4,6). These features led to speculation on the potential role of MEF2C in the architechtonics of the cerebral cortex (2).…”

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confidence: 99%

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

Radford

Ragusa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

221

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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.neurogenesis ͉ synaptogenesis ͉ autism ͉ Rett syndrome K nockdown of the transcription factor MEF2C in mature cerebrocortical neurons results in increased synaptic number and activity (1). To facilitate analysis of MEF2C function in early neuronal development, we engineered a conditional knockout in NSCs by crossing floxed Mef2c mice with Nestin-Cre mice. In contrast to the findings in more mature neurons, we found a striking alteration in the distribution of new neurons in the neocortex and the opposite effect on synaptic activity, i.e., decreased neurotransmission persisting into adulthood.MEF2C belongs to the myocyte enhancer factor 2 (MEF2) subfamily of the MADS (MCM1-agamous-deficiens-serum response factor) gene family (2, 3). We cloned MEF2C from developing mouse brain, and Eric Olson and colleagues then discovered it in the heart (2, 4, 5). In cerebrocortex, MEF2 transcriptional activity is restricted to differentiated cortical neurons in a specific laminar pattern, and its distribution increases along the rostrocaudal axis (2, 4, 6). These features led to speculation on the potential role of MEF2C in the architechtonics of the cerebral cortex (2). Previous studies demonstrated an important role for MEF2C in heart development (7). In the CNS, MEF2C is involved in neuronal apoptosis (8) and synapse formation (1, 9) in vitro or in brain slices. Most recently, our laboratory discovered that a constitutively active form of MEF2C induces embryonic stem cells to commit to a neuronal fate in a virtually exclusive fashion (10). However, studies on the effect of endogenous MEF2C on CNS neurons in vivo were impeded by the embryonic lethality of conventional Mef2c-null mice because of cardiovascular defects at embryonic day (E) 9.5, before brain development (7). Here, we report that conditionally knocking out the Mef2c gene in neural progenitors causes abnormal aggregation and compaction of neurons migrating into the lower layers of the neocortex during development. Knockout mice surviving to adulthood manifest smaller, apparently less mature neurons and smaller whole brain size, with resultant aberrant electrophysiology and behavior.

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Section: Mef2c Conditional Knockout Micementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Radford

Ragusa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

221

230

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“…26 Variants of MEF2C were found in the skeletal muscle and brain. Leifer et al 27 found that the brain form was expressed by neurons in particular layers of the cerebral cortex and that expression declined during post-natal development. The gene distal to the breakpoint is CETN3 (centrin, EF-hand protein, 3): the protein encoded by this gene contains four EF-hand calcium-binding domains, and it is a member of the centrin protein family; this was highly enriched in the centrosome fraction of cell extracts and appears to represent the most abundant centrosomal isoform.…”

Section: Mapping Of the 8q23 Translocation Breakpointsmentioning

confidence: 99%

Two patients with balanced translocations and autistic disorder: CSMD3 as a candidate gene for autism found in their common 8q23 breakpoint area

et al. 2008

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Recent studies estimated a rate of 3-5% of cytogenetic abnormalities involving many different chromosomes in autistic spectrum disorders (ASDs). Here, we report on two unrelated male patients with de novo translocations, autistic behaviour and psychomotor delay. These two patients carry a balanced chromosome translocation t(5;8)(q14.3;q23.3) and t(6;8)(q13;q23.2), respectively. A detailed physical map covering the regions involved in the translocations was constructed using BAC clones mapping on chromosomes 5q14.3, 6q13 and 8q23. Fluorescence in situ hybridisation (FISH) analyses were carried out using these genomic clones. We fine mapped the two translocation breakpoints on chromosomes 8 identifying their position within a short 5 Mb genomic region. Breakpoints on chromosomes 8 in both patients do not interrupt any known gene but both map in a region containing the CSMD3 gene, which thereby can be considered as a candidate for ASDs.

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Collaborative interactions between MEF-2 and Sp1 in muscle-specific gene regulation

1998

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Previous investigations have demonstrated synergistic interactions in vivo between CCAC and A/T-rich nucleotide sequence motifs as functional components of muscle-specific transcriptional enhancers. Using CCAC and A/T-rich elements from the myoglobin and muscle creatine kinase (MCK) gene enhancers, Sp1 and myocyte-specific enhancer factor-2 (MEF-2) were identified as cognate binding proteins that recognize these sites. Physical interactions between Sp1 and MEF-2 were demonstrated by immunological detection of both proteins in DNA binding complexes formed in vitro by nuclear extracts in the presence of only the A/T sequence motif, by coprecipitation of recombinant MEF-2 in the presence of a glutathione-S-transferase-Sp1 fusion protein bound to glutathione beads, and by a two-hybrid assay in Saccharomyces cerevisiae. The interaction with Sp1 in vitro and in vivo is specific for MEF-2 and was not observed with serum response factor, a related MADS domain protein. Forced expression of Sp1 and MEF-2 in insect cells otherwise lacking these factors promotes synergistic transcriptional activation of a promoter containing binding sites for both proteins. These data expand the repertoire of functional and physical interactions between lineage-restricted (MEF-2) and ubiquitous (Sp1) transcription factors that may be important for myogenic differentiation.

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MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex.

Cited by 203 publications

References 27 publications

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

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

Two patients with balanced translocations and autistic disorder: CSMD3 as a candidate gene for autism found in their common 8q23 breakpoint area

Collaborative interactions between MEF-2 and Sp1 in muscle-specific gene regulation

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