In Vivo Analysis of MEF2 Transcription Factors in Synapse Regulation and Neuronal Survival

Akhtar, Mohd Waseem; Kim, Mi Sung; Adachi, Megumi; Morris, Michael J.; Qi, Xiaoxia; Richardson, James A.; Bassel‐Duby, Rhonda; Olson, Eric N.; Kavalali, Ege T.; Monteggia, Lisa M.

doi:10.1371/journal.pone.0034863

Cited by 97 publications

(104 citation statements)

References 21 publications

(37 reference statements)

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“…For tumors, transgenic mice were subcutaneously injected with 100 µL of BD Matrigel basement membrane matrix (BD) containing 1 × 10 5 B16F10 melanoma cells and harvested at 12-mm diameter. iEC Mef2A/C knockout embryos and pups were obtained by crossing Mef2A flox/flox ;Mef2C flox/flox mice (Vong et al 2005;Akhtar et al 2012) with Cdh5(PAC)…”

Section: Animalsmentioning

confidence: 99%

MEF2 transcription factors are key regulators of sprouting angiogenesis

et al. 2016

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Angiogenesis, the fundamental process by which new blood vessels form from existing ones, depends on precise spatial and temporal gene expression within specific compartments of the endothelium. However, the molecular links between proangiogenic signals and downstream gene expression remain unclear. During sprouting angiogenesis, the specification of endothelial cells into the tip cells that lead new blood vessel sprouts is coordinated by vascular endothelial growth factor A (VEGFA) and Delta-like ligand 4 (Dll4)/Notch signaling and requires high levels of Notch ligand DLL4. Here, we identify MEF2 transcription factors as crucial regulators of sprouting angiogenesis directly downstream from VEGFA. Through the characterization of a Dll4 enhancer directing expression to endothelial cells at the angiogenic front, we found that MEF2 factors directly transcriptionally activate the expression of Dll4 and many other key genes up-regulated during sprouting angiogenesis in both physiological and tumor vascularization. Unlike ETS-mediated regulation, MEF2-binding motifs are not ubiquitous to all endothelial gene enhancers and promoters but are instead overrepresented around genes associated with sprouting angiogenesis. MEF2 target gene activation is directly linked to VEGFA-induced release of repressive histone deacetylases and concurrent recruitment of the histone acetyltransferase EP300 to MEF2 target gene regulatory elements, thus establishing MEF2 factors as the transcriptional effectors of VEGFA signaling during angiogenesis.

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Section: Animalsmentioning

confidence: 99%

MEF2 transcription factors are key regulators of sprouting angiogenesis

et al. 2016

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“…To determine the potential functions of individual MEF2 factors in adult skeletal muscle regeneration, we generated mice with conditional null alleles of Mef2a, c, and d and bred them to Pax7-CreERT2 mice, which contain a tamoxifen-inducible Cre recombinase-estrogen receptor fusion protein cassette within the Pax7 allele (16). Details of the conditional Mef2 alleles have been described (17)(18)(19). Because Pax7 is expressed in both quiescent and activated satellite cells, Pax7-CreERT2 mice allow for inducible Cre-mediated gene deletion specifically in satellite cells (16).…”

Section: Redundant Functions Of Mef2a C and D During Adult Skeletalmentioning

confidence: 99%

Requirement of MEF2A, C, and D for skeletal muscle regeneration

Liu

Nelson

Bezprozvannaya

et al. 2014

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

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179

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Regeneration of adult skeletal muscle following injury occurs through the activation of satellite cells, an injury-sensitive muscle stem cell population that proliferates, differentiates, and fuses with injured myofibers. Members of the myocyte enhancer factor 2 (MEF2) family of transcription factors play essential roles in muscle differentiation during embryogenesis, but their potential contributions to adult muscle regeneration have not been systematically explored. To investigate the potential involvement of MEF2 factors in muscle regeneration, we conditionally deleted the Mef2a, c, and d genes, singly and in combination, within satellite cells in mice, using tamoxifen-inducible Cre recombinase under control of the satellite cell-specific Pax7 promoter. We show that deletion of individual Mef2 genes has no effect on muscle regeneration in response to cardiotoxin injury. However, combined deletion of the Mef2a, c, and d genes results in a blockade to regeneration. Satellite cell-derived myoblasts lacking MEF2A, C, and D proliferate normally in culture, but cannot differentiate. The absence of MEF2A, C, and D in satellite cells is associated with aberrant expression of a broad collection of known and unique protein-coding and long noncoding RNA genes. These findings reveal essential and redundant roles of MEF2A, C, and D in satellite cell differentiation and identify a MEF2-dependent transcriptome associated with skeletal muscle regeneration. myogenesis | myogenic regulatory factor | myotube

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“…The MEF2 family of transcription factors contains four members that have high homology in their DNA binding domains. MEF2C is the major form expressed in the cortex and has been shown to play a predominant role in neuronal synapse development and function (55). A fusion of the MEF2C DNA-binding and dimerization domain with the VP16 activation domain serves as an activator of MEF2 target genes and bypasses the need for MEF2-specific coactivators (25).…”

Section: E185 Control or Baf53b-cre Brg1mentioning

confidence: 99%

Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling

Zhang

Cao

Chang

et al. 2016

Molecular and Cellular Biology

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Synapse development requires normal neuronal activities and the precise expression of synapse-related genes. Dysregulation of synaptic genes results in neurological diseases such as autism spectrum disorders (ASD). Mutations in genes encoding chromatin-remodeling factor Brg1/SmarcA4 and its associated proteins are the genetic causes of several developmental diseases with neurological defects and autistic symptoms. Recent large-scale genomic studies predicted Brg1/SmarcA4 as one of the key nodes of the ASD gene network. We report that Brg1 deletion in early postnatal hippocampal neurons led to reduced dendritic spine density and maturation and impaired synapse activities. In developing mice, neuronal Brg1 deletion caused severe neurological defects. Gene expression analyses indicated that Brg1 regulates a significant number of genes known to be involved in synapse function and implicated in ASD. We found that Brg1 is required for dendritic spine/synapse elimination mediated by the ASDassociated transcription factor myocyte enhancer factor 2 (MEF2) and that Brg1 regulates the activity-induced expression of a specific subset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interacts with MEF2 and that MEF2 is required for Brg1 recruitment to target genes in response to neuron activation. Thus, Brg1 plays important roles in both synapse development/maturation and MEF2-mediated synapse remodeling. Our study reveals specific functions of the epigenetic regulator Brg1 in synapse development and provides insights into its role in neurological diseases such as ASD. Synapses formed between axons and dendrites connect neurons and generate neural circuits that control brain functions (1). The dysregulation of synapse formation, maturation, or plasticity causes many neurodevelopmental diseases such as autism (2). Autism spectrum disorders (ASDs) are complex diseases characterized by a range of behavior abnormalities and regulated by genetic and epigenetic factors (3-5). In ASDs with various genetic or environmental causes, synaptic dysfunction is a central defect.Many autism risk genes encode transcription factors and epigenetic regulators, which likely function to regulate the expression of synaptic genes (4, 6, 7). A gene network analysis predicted the core subunit of a SWI/SNF-like BRG1-associated factor (BAF) ATP-dependent chromatin remodeling complex, Brg1/SmarcA4, as one of the key nodes in autism pathogenesis (7). BAF complexes containing the ATPase Brg1 or Brm use energy derived from ATP hydrolysis to modulate chromatin structures and regulate transcription (8-10). Mutations in several BAF subunits are the genetic causes of Coffin-Siris syndrome and Nicolaides-Baraitser syndrome with autistic symptoms such as intellectual disability and delayed speech (11-15). In addition, de novo functional mutations of genes encoding several BAF subunits are identified repeatedly in autism patients (7,(16)(17)(18). Mutations in a gene encoding the BAF-associated protein activity-dependent ...

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In Vivo Analysis of MEF2 Transcription Factors in Synapse Regulation and Neuronal Survival

Cited by 97 publications

References 21 publications

MEF2 transcription factors are key regulators of sprouting angiogenesis

MEF2 transcription factors are key regulators of sprouting angiogenesis

Requirement of MEF2A, C, and D for skeletal muscle regeneration

Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling

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