Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development.
Shaun Hurley, Conor Mohan, Philipp Suetterlin and 13 others
PMID 33627187WHAT IT FOUND
The autism-associated factor CHD8 affects mouse brain development in a threshold way.
Mild loss enlarged brains by increasing progenitor growth, severe loss made brains smaller through cell death. This does not test human therapy.
Key findings
01CHD8 dosage produced non-linear brain size effects in mice. Mild hypomorphs had increased brain size, while severe hypomorphs and conditional knockouts had smaller brain size.
02Chd8 neo/neo showed 2209 differentially expressed genes, compared with 14 in Chd8 +/−. Many gene expression changes appeared only when CHD8 fell below 50%.
03Conditional CHD8 loss in neural progenitors caused pronounced brain hypoplasia. Reducing p53 partially rescued this phenotype.
STILL TO COME
How it was doneWhat they found
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What it does not show
The work was done in mice, not people, so it does not show how therapists should treat patients. All mouse studies used one genetic background, so results may differ in other strains. Mild hypomorphs had reduced postnatal survival, so only surviving mice could be behaviourally tested. Developmental and molecular experiments used mixed-sex samples, so sex-specific effects cannot be ruled out. Mouse and human brain development differ, so the relevance to human cortical expansion is not proven.
Declared interests
Funding was from the Medical Research Council, Simons Foundation Autism Research Initiative, Ontario Brain Institute POND programme, and King's Bioscience Institute and Guy's and St Thomas' Charity PhD programme. The supplied text does not state author competing interests.
The easy way to misread this
Do not conclude that CHD8 dosage findings provide guidance for autism therapy. The study tested mouse brain development and gene expression, not human patients, clinical outcomes, or treatments.