Non-monotonic regulation of gene expression, neural progenitor fate and brain growth by the chromatin remodeller CHD8

Heterozygous CHD8 mutations are associated with autism and macrocephaly with high penetrance in the human population. The reported mutations may have loss-of-function (haploinsufficient), hypomorphic or dominant negative effects on protein function. To determine the effects of reducing CHD8 protein function below haploinsufficient levels on brain development, we established a Chd8 allelic series in the mouse. Chd8 heterozygous mice exhibited relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. In comparison, mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia, and significantly altered expression of over 2000 genes. Autism-associated genes were downregulated and neural progenitor proliferation genes upregulated. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, affecting genes and pathways that largely overlapped with those dysregulated in the mild hypomorphs. By contrast, homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in the induction of p53 target genes, cell cycle exit, apoptosis and pronounced brain hypoplasia. Intriguingly, increased progenitor proliferation in hypomorphs was primarily restricted to TBR2+ intermediate progenitors, suggesting critical roles for CHD8 in regulating the expansion of this population. Given the importance of these progenitors in human cortical growth, this observation suggests that human brain development might be more sensitive to CHD8 deficiency than the mouse. We conclude that brain development is acutely sensitive to CHD8 dosage and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage can result in non-linear effects on gene transcription and brain growth.