The expression of MEF2 genes is implicated in CNS neuronal differentiation

Lin, Xi; Shah, Sanjivkmar; Bulleit, Robert F.

doi:10.1016/s0169-328x(96)00135-0

Cited by 90 publications

(80 citation statements)

References 33 publications

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“…Because cortex contains a relatively higher level of MEF2C protein, whereas cerebellum contains a relatively higher level of MEF2A protein (ref. 47; Z.M., unpublished data), the MEF2C isoform is likely to contribute to the BDNF͞ERK5͞MEF2-survival pathway.…”

Section: Discussionmentioning

confidence: 94%

ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons

Liu

Cavanaugh

Wang

et al. 2003

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

154

176

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Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase family whose biological function in the CNS has not been defined. In contrast to ERK1 and ERK2, which are activated by neurotrophins (NTs), cAMP, and neuronal activity in cortical neurons, ERK5 is activated only by NTs. Here, we report that ERK5 expression is high in the brain during early embryonic development but declines as the brain matures to almost undetectable levels by postnatal day (P) 49. Interestingly, expression of a dominant-negative ERK5 blocked brain-derived neurotrophic factor protection against trophic withdrawal in primary cortical neurons cultured from embryonic day (E) 17 but not P0. Furthermore, expression of a dominant-negative ERK5 induced apoptosis in E17 but not P0 cortical neurons maintained in the presence of serum. We also present evidence that ERK5 protection of E17 cortical neurons may be mediated through myocyte enhancer factor 2-induced gene expression. These data suggest that ERK5 activation of myocyte enhancer factor 2-induced gene expression may play an important and novel role in the development of the CNS by mediating NT-promoted survival of embryonic neurons.N eurotrophins (NTs) have profound effects on the development of the CNS and regulate differentiation, survival, and adaptive responses of neurons. For example, NTs protect many types of neurons from apoptosis both during development and in the adult (1-6). Consequently, there is an intense interest in elucidating mechanisms for NT-mediated neuroprotection and its contribution to the development of the CNS. NTs including nerve growth factor, brain-derived neurotrophic factor (BDNF), NT3, NT4͞5, and NT6 bind to and activate specific receptor tyrosine kinases of the Trk family (7,8). Upon binding to and activating Trk, NTs can activate several intracellular signaling transduction systems including the phosphatidylinositol 3-kinase, protein kinase C, and extracellular signal-regulated kinase 1͞2 (ERK1͞2) pathways (8-11).Recently, a new member of the mitogen-activated protein (MAP) kinase family, ERK5 (also known as the big MAP kinase 1 or BMK1) was discovered (12, 13). ERK5 is widely expressed in many tissues including brain. Although ERK5 contains a similar TEY dual-phosphorylation motif as ERK1͞2 and the N-terminal half of ERK5 shares sequence homology with other members of the MAP kinase family, a large C terminus and a unique loop-12 sequence distinguish it from ERK1͞2 and other MAP kinase family members. ERK5 is phosphorylated and activated by MAP kinase kinase (MEK) 5, but not by MEK1 or MEK2 (12,14). MEK5 is specific for ERK5 and does not phosphorylate ERK1͞2, c-Jun N-terminal protein kinase, or p38 MAP kinase (12,14). A number of substrates have been identified for activated ERK5 including myocyte enhancer factor 2C (MEF2C) (15-17). Like ERK1͞2, ERK5 is activated by serum, epidermal growth factor, nerve growth factor, and G protein-coupled receptors (15)(16)(17)(18)(19). In contrast to ERK1 and ERK2, which are activat...

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Section: Discussionmentioning

confidence: 94%

ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons

Liu

Cavanaugh

Wang

et al. 2003

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

154

176

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“…Previous studies including our own have shown that MEF2A protein is expressed by cerebellar granule neurons in vivo and in vitro (21)(22)(23)(24). 2 Our recent work has demonstrated that expression from the MEF2 reporter gene is activated in granule neurons cultured in the presence of KCl and the enhanced expression requires MEF2 DNA-binding sites.…”

Section: Membrane Depolarization-dependent Mef2 Reporter Genementioning

confidence: 90%

Calcineurin Enhances MEF2 DNA Binding Activity in Calcium-dependent Survival of Cerebellar Granule Neurons

Mao

Wiedmann²

1999

Journal of Biological Chemistry

143

136

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Myocyte enhancer factor 2 (MEF2) has been shown recently to be necessary for mediating activity-dependent neuronal survival. In this study, we show that calcium signals regulate MEF2 activity through a serine/ threonine phosphatase calcineurin. In cultured primary cerebellar granule neurons, the electrophoretic mobility of MEF2A protein was sensitive to the level of extracellular potassium chloride (

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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%

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.

234

230

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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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The expression of MEF2 genes is implicated in CNS neuronal differentiation

Cited by 90 publications

References 33 publications

ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons

ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons

Calcineurin Enhances MEF2 DNA Binding Activity in Calcium-dependent Survival of Cerebellar Granule Neurons

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

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