Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling
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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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The Wnt signaling pathway plays a crucial role in neuronal progenitor proliferation and differentiation in the forebrain.
“One of the risk genes, Chd8, encodes a protein that binds directly to β-catenin to recruit histone proteins and negatively regulates the Wnt signaling pathway, which plays a crucial role in neuronal progenitor proliferation and differentiation in the forebrain (39–42).”
From In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes (2020) · cites this paper as [41]
Chd8 encodes a protein that binds directly to β-catenin to recruit histone proteins and negatively regulates the Wnt signaling pathway.
“One of the risk genes, Chd8, encodes a protein that binds directly to β-catenin to recruit histone proteins and negatively regulates the Wnt signaling pathway, which plays a crucial role in neuronal progenitor proliferation and differentiation in the forebrain (39–42).”
From In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes (2020) · cites this paper as [41]
Knockdown of CHD8 in adult mice leads to disruption of Wnt signaling and abnormal neural progenitor cell proliferation.
“For example, knockdown of CHD8 in adult mice leads to a disruption of Wnt signaling and abnormal NPC proliferation (Durak et al., 2016).”
From Getting to the cores of autism (2019) · cites this paper as Durak et al., 2016
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- Authors
- Durak, O., Gao, F., Kaeser-Woo, Y. J., Rueda, R., Martorell, A. J., Nott, A., Liu, C. Y., Watson, L. A., & Tsai, L.-H.
- Affiliations
- Massachusetts Institute of Technology (US)
- Broad Institute (US)
- Corresponding author
- Tsai, Li-Huei
- Venue
- Nature Neuroscience
- Published
- 2016-10-03
- Volume
- 19
- Issue
- 11
- Pages
- 1477-1488
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC5386887
- OpenAlex
- W2528582931
- Cited by
- 243
- References
- 60
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 17 · 2023: 20 · 2022: 25 · 2021: 27 · 2020: 39 · 2019: 24 · 2018: 27 · 2017: 25 · 2016: 4 · 2014: 1
- FWCI
- 13.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- PMC
- Funders
- National Institutes of Health (5u01mh106018-03)
- National Institute of Mental Health (U01-MH106018)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- CHD8, cortical neurogenesis, autism spectrum disorder, de novo mutations, neural progenitor proliferation, neural progenitor differentiation, Wnt signaling, polycomb repressive complex 2, cell cycle genes, neuronal morphology, transcriptional regulation, brain development
- MeSH terms
- Autism Spectrum Disorder, Animals, Cell Cycle, Cell Differentiation, Cell Division, DNA-Binding Proteins, Female, Transcription, Genetic, Gene Expression Regulation, Developmental, Mice, Neurogenesis, Neural Stem Cells, Wnt Signaling Pathway
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