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| Status |
Public on Oct 24, 2020 |
| Title |
MEF2C hypofunction in neuronal and neuroimmune populations produces MEF2C haploinsufficiency syndrome behaviors in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
We compared gene expression profiles between control and Mef2c heterozygous mice. We analyzed genome-wide expression levels from cortical tissue from 4 Mef2c heterozygous mice compared with 4 control mice. Gene expression was balanced for technical and biological covaraites.
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| Contributor(s) |
Berto S, Harrington AK, Bridges CM, Konopka G, Cowan CW |
| Citation(s) |
32418612 |
| Submission date |
Oct 25, 2019 |
| Last update date |
Jan 23, 2021 |
| Contact name |
Genevieve Konopka |
| E-mail(s) |
gena@alum.mit.edu
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| Organization name |
UT Southwestern Medical Center
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| Department |
Neuroscience
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| Street address |
5323 Harry Hines Blvd.
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| City |
Dallas |
| State/province |
TX |
| ZIP/Postal code |
75390-9111 |
| Country |
USA |
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| Platforms (1) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA579584 |
| SRA |
SRP227037 |
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