MEF2C hypofunction in neuronal and neuroimmune populations produces MEF2C haploinsufficiency syndrome behaviors in mice
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ABSTRACT:
PROVIDER: PRJNA579584 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR10349468.fastq.gz | Fastqsanger.gz | |||
| SRR10349469.fastq.gz | Fastqsanger.gz | |||
| SRR10349470.fastq.gz | Fastqsanger.gz | |||
| SRR10349471.fastq.gz | Fastqsanger.gz | |||
| SRR10349472.fastq.gz | Fastqsanger.gz |
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Project description:Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). Here, we show that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) display numerous MCHS-like behaviors, including autism-related behaviors, as well as deficits in cortical excitatory synaptic transmission. We find that hundreds of genes are dysregulated in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observe an enrichment of upregulated microglial genes, but not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduces a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduces social deficits and repetitive behavior. Together our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.
2020-10-24 | GSE139419 | GEO
Project description:BackgroundMicrodeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). MEF2C hypofunction in neurons is presumed to underlie most of the symptoms of MCHS. However, it is unclear in which cell populations MEF2C functions to regulate neurotypical development.MethodsMultiple biochemical, molecular, electrophysiological, behavioral, and transgenic mouse approaches were used to characterize MCHS-relevant synaptic, behavioral, and gene expression changes in mouse models of MCHS.ResultsWe showed that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) displayed numerous MCHS-related behaviors, including autism-related behaviors, changes in cortical gene expression, and deficits in cortical excitatory synaptic transmission. We detected hundreds of dysregulated genes in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observed an enrichment of upregulated microglial genes, but this was not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduced a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduced social deficits and repetitive behavior.ConclusionsTaken together, our findings show that mutations found in individuals with MCHS disrupt the DNA-binding function of MEF2C, and DNA binding-deficient Mef2c global heterozygous mice display numerous MCHS-related phenotypes, including excitatory neuron and microglia gene expression changes. Our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.
| S-EPMC7483399 | biostudies-literature
Project description:Heterozygous loss-of-function mutations or deletions of the MEF2C gene cause a neurodevelopmental disorder, termed MEF2C Haploinsufficiency syndrome (MCHS), that is characterized by autism spectrum disorder, intellectual disability, seizures, and other neurological symptoms. In mice, global Mef2c heterozygosity produces numerous behavioral phenotypes reminiscent of MCHS. MEF2C is highly expressed in multiple cell populations in the developing brain, including GABAergic inhibitory neurons. While MEF2C hypofunction in excitatory neurons or microglia alter neurotypical behaviors and brain circuit function, the impact of MEF2C heterozygosity in GABAergic neurons remains unknown.
2025-04-30 | GSE230873 | GEO
Project description:Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) – a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice.
2016-09-23 | GSE87202 | GEO
Project description:Recent studies revealed that microdeletion of human chromosome 5q14.3 leads to the occurrence of neurodevelopmental disorders such as autism and intellectual disability, and have identified Mef2c haploinsufficiency as a main cause. Here, we found that a brain-enriched long non-coding RNA, termed NDIME, is located near the Mef2c locus and is required for normal neural differentiation of mouse embryonic stem cells (mESCs). Mechanistic studies showed that exons 1-3 of NDIME interacts with the major component of polycomb repressive complex 2 (PRC2) EZH2, blocking EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) at the Mef2c promoter, ensuring Mef2c transcription. Moreover, both the expression levels of NDIME and Mef2c were significantly downregulated in the hippocampus of autism model mice, while adeno-associated virus (AAV)-mediated expression of NDIME significantly increased the Mef2c expression and ameliorated autism-like behaviors. Collectively, our findings reveal an epigenetic mechanism of NDIME regulating Mef2c transcription and neural differentiation, and the potential effects and application of the NDIME/Mef2c axis in autism.
2020-11-03 | GSE143606 | GEO
Project description:Chromosome 5q14.3 harbored an unusual but genome-wide significant excess of noncoding BCA breakpoints that did not directly disrupt MEF2C. This distribution of breakpoints in proximity but not directly disruptive to MEF2C was further supported by microdeletions in NDD cases reported in DECIPHER34. In considering the landscape of de novo SVs across the 5q14.3 locus in NDD cases, the primary unifying thread appears to be distal boundary disruption. Taken together, these data provide compelling clinical genetic and statistical genomics evidence suggesting that both direct disruption of MEF2C and alterations to this gene’s encompassing 3D regulatory architecture may result in comparable molecular mechanisms in NDD cases. Motivated by these findings, we have performed a systematic molecular dissection of the 5q14.3 locus to quantify the transcriptomic and electrophysiological effects of MEF2C LoF in human neural derivatives. Through the generation of an allelic series of CRISPR-engineered human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) and glutamatergic neurons (iNs), we interrogated the impact of enhancer, TAD boundary, and loop boundary deletion on local genome organization, local expression effects on MEF2C, and global transcriptional signatures. Our analyses reveal that direct MEF2C alteration results in both transcriptional and functional changes to the synapse. Moreover, we find that disruption of the distal boundary of the MEF2C-containing loop is insufficient to produce indirect MEF2C haploinsufficiency. By contrast, disruption of the proximal boundary of the same 3D structure results in haploinsufficiency of MEF2C that is comparable to direct gene disruption. Overall, these data suggest that the effects of direct and indirect MEF2C disruption contribute to cell type-specific alterations on neuronal functions that converge on synaptic deficits in neurodevelopment.
2022-06-10 | GSE204778 | GEO
Project description:Characterization of molecular changes associated with Mef2c hypofunction in the mouse auditory nerve
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Project description:In acute myeloid leukemia, chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that transgenic Mef2cS222A/S222A mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance, induced by MARK kinases in cells, and blocked by selective MARK inhibitor MRT199665, which caused apoptosis of MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C. These findings identify signaling-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease.
2018-07-23 | GSE94453 | GEO
Project description:The transcription factor MEF2C is specifically induced by VEGF in endothelial cells. To delineate target genes of MEF2C in endothelial cells, which might be important during angiogenesis also, MEF2C was overexpressed adenovirally in human umbilical vein endothelial cells (HUVECs) over a period of 8 to 32 hours. Expression data should be compared to control infected cells, to discriminate against virally induced genes, and should be further compared to HUVECs infected with an adenovirus encoding for a dominant-negative form of MEF2. HUVECs of the same batch, passage 3 were infected with Ad.con, Ad.MEF2C or Ad.DNMEF2 for 8, 16 or 32 hours for RNA extraction and hybridization on Affymetrix microarrays.
2013-06-01 | E-GEOD-46279 | biostudies-arrayexpress