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Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development
Shaun Hurley1, Conor Mohan1, Philipp Suetterlin1
1Centre for Craniofacial and Regenerative Biology, King's College London, London, UK.
Molecular Autism
|February 25, 2021
Summary
CHD8 haploinsufficiency causes autism. New mouse models reveal CHD8 dosage impacts brain development, affecting gene expression and progenitor cell fate, with varying effects on brain size.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- CHD8 haploinsufficiency is linked to autism and macrocephaly in humans.
- Heterozygous Chd8 mice show subtle brain overgrowth and minimal gene expression changes in embryonic development.
Purpose of the Study:
- To create sub-haploinsufficient Chd8 mouse models.
- To investigate CHD8 functions during embryonic cortical development.
Main Methods:
- Generated Chd8-deficient mice with reduced protein levels (35%, 10%, and 0%).
- Utilized RNA sequencing, structural MRI, and immunostaining to analyze gene expression, brain size, and neural progenitor fate.
Main Results:
- Mild Chd8 hypomorphs exhibited postnatal lethality and brain hyperplasia with over 2000 dysregulated genes.
- Severe hypomorphs showed increased p53 pathway activity, reduced brain size, and apoptosis.
- Conditional knockouts displayed brain hypoplasia due to p53 pathway activation and apoptosis.
Conclusions:
- CHD8 dosage critically influences p53 pathway repression, neurodevelopmental gene expression, and neural progenitor fate.
- Embryonic brain development is highly sensitive to CHD8 expression levels.
- Dosage-dependent effects of CHD8 lead to non-linear outcomes in gene transcription and brain growth.
Keywords:
ApoptosisAutismCHD8ChromatinConditional knockoutCortexGene expressionHypomorphIntermediate progenitorMouseNeural progenitorProliferationTBR2p53More Related Videos
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