Chd8 Mediates Cortical Neurogenesis Via Transcriptional Regulation of Cell Cycle and Wnt Signaling

Overview

Journal Nat Neurosci

Date 2016 Oct 4

PMID 27694995

Citations 124

Authors

Omer Durak

Fan Gao

Yea Jin Kaeser-Woo

Richard Rueda

Anthony J Martorell

Alexi Nott

Carol Y Liu

L Ashley Watson

Li-Huei Tsai

Affiliations

Soon will be listed here.

Abstract

De novo mutations in CHD8 are strongly associated with autism spectrum disorder, but the basic biology of CHD8 remains poorly understood. 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 while Chd8 stimulates the transcription of cell cycle genes, it also 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 Chd8 expression during development help negotiate the fine balance between neural progenitor proliferation and differentiation. Together, these observations provide new insights into the neurodevelopmental role of Chd8.

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