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Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development

Research output: Contribution to journalArticlepeer-review

Shaun Hurley, Conor Mohan, Philipp Suetterlin, Robert Ellingford, Kimberley L H Riegman, Jacob Ellegood, Angela Caruso, Caterina Michetti, Olivier Brock, Romy Evans, Fabrizio Rudari, Alessio Delogu, Maria Luisa Scattoni, Jason P Lerch, Cathy Fernandes, M Albert Basson

Original languageEnglish
Article number16
Pages (from-to)16
JournalMolecular Autism
Volume12
Issue number1
DOIs
Accepted/In press21 Dec 2020
Published24 Feb 2021

Bibliographical note

Funding Information: This work was supported by research grants from the Medical Research Council (MR/K022377/1, MAB and CF), Simons Foundation (SFARI #344763 and #653443, MAB) and Ontario Brain Institute’s POND programme (JPL). SH and RE were supported by the King’s Bioscience Institute and the Guy’s and St Thomas' Charity Prize PhD Programme in Biomedical and Translational Science. Funding Information: We thank Elizabeth Robertson (University of Oxford) for the Sox1-Cre mouse line and Alex Donovan for technical assistance. We acknowledge the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust Grant Reference 090532/Z/09/Z) for the generation of the RNA sequencing data and Drs. Brian Nieman and Leigh Spencer Noakes for their MRI sequences. We thank Anthony Graham, Clemens Kiecker and Jeremy Green for critical comments on the manuscript. Funding Information: We thank Elizabeth Robertson (University of Oxford) for the Sox1-Cre mouse line and Alex Donovan for technical assistance. We acknowledge the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust Grant Reference 090532/Z/09/Z) for the generation of the RNA sequencing data and Drs. Brian Nieman and Leigh Spencer Noakes for their MRI sequences. We thank Anthony Graham, Clemens Kiecker and Jeremy Green for critical comments on the manuscript. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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  • Hurley_Mol Autism_accepted

    Hurley_Mol_Autism_accepted.pdf, 25.5 MB, application/pdf

    Uploaded date:31 Dec 2020

    Version:Accepted author manuscript

King's Authors

Abstract

BACKGROUND: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development.

METHODS: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate.

RESULTS: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice.

CONCLUSIONS: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work.

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