MEF2C hypofunction in neuronal and neuroimmune populations produces MEF2C haploinsufficiency syndrome behaviors in mice
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PROVIDER: PRJNA579584 | ENA |
REPOSITORIES: ENA
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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: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:We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Adult Chd8+/del5 mice exhibited cognitive impairment correlated with increased cerebral cortex, hippocampus, and amygdala volume, but displayed normal social interactions and no repetitive behaviors. Network analysis of neurodevelopmental gene expression revealed widespread transcriptional changes in Chd8+/del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes, and neuroimmune signaling. Among gene co-expression networks, we identified a module with peak expression in early brain development that featured dysregulation of genes enriched for promoter binding by Chd8 and associated with RNA processing, chromatin remodeling, and cell cycle. We validated increased neuronal proliferation and splicing alterations during Chd8+/del5 brain development. Our results show that Chd8+/del5 mice exhibit neurodevelopmental changes paralleling humans with CHD8 mutations and highlight widespread pathological consequences of Chd8 haploinsufficiency.
2017-06-21 | GSE99331 | GEO
Project description:Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice
| PRJNA495634 | ENA
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:SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multi electrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5+/- cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5+/- cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5+/- animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5+/- adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.
2018-10-10 | GSE121099 | GEO
Project description:SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multi electrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5+/- cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5+/- cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5+/- animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5+/- adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.
2018-10-10 | GSE120960 | GEO