Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling.
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.
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.
Omer
O
Durak
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.
Fan
F
Gao
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.
Yea Jin
YJ
Kaeser-Woo
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.
Richard
R
Rueda
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.
Anthony J
AJ
Martorell
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.
Alexi
A
Nott
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.
Carol Y
CY
Liu
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.
L Ashley
LA
Watson
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts USA.
Li-Huei
LH
Tsai
D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway / Q000235:genetics*
D004268:DNA-Binding Proteins; C515814:duplin protein, mouse
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