Chd8 mediates cortical neurogenesis through transcriptional regulation of cell cycle and Wnt signaling genes

De novo mutations in CHD8 are strongly associated with autism spectrum disorder (ASD), however the underlying mechanisms remain elusive. Here we report that Chd8 knockdown during cortical development results in defective neural progenitor proliferation and differentiation that ultimately manifests in abnormal neuronal morphology and behaviors in adult mice. Transcriptome analysis revealed that on the one hand Chd8 stimulates the transcription of cell cycle genes, while on the other it precludes the induction of neural specific genes by regulating the expression of PRC2 complex components. Furthermore, knockdown of Chd8 disrupts the expression of key transducers of Wnt signaling, and enhancing Wnt signaling rescues the transcriptional and behavioral deficits caused by Chd8 knockdown. We propose that these roles of Chd8 and the dynamics of its expression during development help negotiate the fine balance between neural progenitor proliferation and differentiation. Together, these observations provide new insights into the etiology of ASD. In utero electroporation of cortical radial glial cells with either control or Chd8 shRNA. Cortices from 3-5 embryos were pooled per biological replicates (three biological replicates for Chd8 sh1, and two biological replicates for Chd8 sh2), followed by FAC sorting of GFP positive cells.