Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits

Platt, Randall J.; Zhou, Yang; Slaymaker, Ian M.; Shetty, Ashwin S.; Weisbach, Niels R.; Kim, Jin-Ah; Sharma, Jitendra; Desai, Mitul; Sood, Sabina; Kempton, Hannah R.; Crabtree, Gerald R.; Feng, Guoping; Zhang, Feng

doi:10.1016/j.celrep.2017.03.052

Cited by 240Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchGenomic variations and chromosomal abnormalities

Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits

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Platt, Randall J., Zhou, Yang, Slaymaker, Ian M., Shetty, Ashwin S., Weisbach, Niels R., Kim, Jin-Ah, Sharma, Jitendra, Desai, Mitul +5 more·2017·Cell Reports

DOI 10.1016/j.celrep.2017.03.052PMC PMC5455342

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Abstract

Autism spectrum disorder (ASD) is a heterogeneous disease, but genetically defined models can provide an entry point to studying the molecular underpinnings of this disorder. We generated germline mutant mice with loss-of-function mutations in Chd8 , a de novo mutation strongly associated with ASD, and demonstrate that these mice display hallmark ASD behaviors, macrocephaly, and craniofacial abnormalities similar to patient phenotypes. Chd8 +/– mice display a broad, brain-region-specific dysregulation of major regulatory and cellular processes, most notably histone and chromatin modification, mRNA and protein processing, Wnt signaling, and cell-cycle regulation. We also find altered synaptic physiology in medium spiny neurons of the nucleus accumbens. Perturbation of Chd8 in adult mice recapitulates improved acquired motor learning behavior found in Chd8 +/– animals, suggesting a role for CHD8 in adult striatal circuits. These results support a mechanism linking chromatin modification to striatal dysfunction and the molecular pathology of ASD.

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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 [39]
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 [39]
Knock-down of the CHD8 ortholog results in macrocephaly in zebrafish and increased brain weight and volume in mice, phenotypes that reflect clinical observations in subjects with loss-of-function mutations in the gene.
“Knock-down of the CHD8 ortholog results in macrocephaly in zebrafish [32, 343] and increased brain weight and volume [187, 287] in mice, phenotypes that reflect clinical observations in subjects with loss-of-function mutations in the gene [32].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [287]

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Authors: Platt, R. J., Zhou, Y., Slaymaker, I. M., Shetty, A. S., Weisbach, N. R., Kim, J.-A., Sharma, J., Desai, M., Sood, S., Kempton, H. R., Crabtree, G. R., Feng, G., & Zhang, F.
Affiliations: Broad Institute (US)
McGovern Institute for Brain Research (US)
ETH Zurich (CH)
Harvard University (US)
Howard Hughes Medical Institute (US)
Massachusetts Institute of Technology (US)
Corresponding author: Platt, Randall J.
Zhang, Feng
ORCID: Platt, Randall J.
Zhou, Yang
Slaymaker, Ian M.
Shetty, Ashwin S.
Kim, Jin-Ah
Sood, Sabina
Crabtree, Gerald R.
Feng, Guoping
Zhang, Feng
Venue: Cell Reports
Publisher: Elsevier BV
Published: 2017-04
Volume: 19
Issue: 2
Pages: 335-350
ISSN: 2211-1247 (ISSN-L)
DOI: 10.1016/j.celrep.2017.03.052
PMC: PMC5455342
OpenAlex: W2606772481
Cited by: 240
References: 67
Citations by year: 2026: 19 · 2025: 19 · 2024: 29 · 2023: 25 · 2022: 26 · 2021: 35 · 2020: 34 · 2019: 19 · 2018: 22 · 2017: 12
FWCI: 15.79
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Cell Reports (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-nd)
ETH Zürich Research Collection
Funders: Zhang laboratory
Feng laboratory
Swanson Biotechnology Center
National Science Foundation (1122374, 2013169249)
ETH Zurich
NCCR
MSE
Simons Center for the Social Brain at MIT
NIMH (F31-MH111157, 5DP1-MH100706, 1R01-MH110049)
HHMI (NS046789)
SFARI
Simons Foundation (306063, 6927482)
McGovern (1631119)
Stanley Center
Nancy Lurie Marks Family Foundation (6928117)
NIH
NSF
New York Stem Cell Foundation
Howard Hughes Medical Institute
Simons
Paul G. Allen Family
Vallee Foundations
Skoltech-MIT Next Generation Program
Stem Cell Foundation-Robertson Investigator
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords: CHD8, autism spectrum disorder, loss-of-function mutations, de novo mutations, macrocephaly, craniofacial anomalies, chromatin modification, histone modifications, Wnt signaling, cell cycle regulation, nucleus accumbens, medium spiny neurons, striatal circuits, motor learning, synaptic physiology
MeSH terms: Autism Spectrum Disorder, Animals, Chromatin, Corpus Striatum, Disease Models, Animal, DNA-Binding Proteins, Histones, Humans, Germ-Line Mutation, Gene Expression Regulation, Developmental, Mice, Megalencephaly, Wnt Signaling Pathway

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Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits

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