Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling
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Author(s)
Durak, Omer
Gao, Fan
Kaeser-Woo, Yea Jin
Rueda IV, Richard
Martorell, Anthony
Nott, Alexander
Liu, Carol Y
Watson, Lauren Ashley
Tsai, Li-Huei
Date Issued
October 2016
Journal
Nature Neuroscience
Publisher
Nature Publishing Group
Citation
Durak, Omer et al. “Chd8 Mediates Cortical Neurogenesis via Transcriptional Regulation of Cell Cycle and Wnt Signaling.” Nature Neuroscience 19, 11 (October 2016): 1477–1488 © Nature America, Inc, part of Springer Nature
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/NN.4400
