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Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons.

ABSTRACT: Background:Mutations in CHD8, chromodomain helicase DNA-binding protein 8, are among the most replicated and common findings in genetic studies of autism spectrum disorder (ASD). The CHD8 protein is believed to act as a transcriptional regulator by remodeling chromatin structure and recruiting histone H1 to target genes. The mechanism by which deficiency of CHD8 causes ASD has not been fully elucidated. Methods:We examined the expression of CHD8 in human and mouse brains using both immunohistochemistry and RNA in situ hybridization. We performed in utero electroporation, neuronal culture, and biochemical analysis using RNAi to examine the functional consequences of CHD8 deficiency. Results:We discovered that CHD8 is expressed highly in neurons and at low levels in glia cells in both humans and mice. Specifically, CHD8 is localized predominately in the nucleus of both MAP2 and parvalbumin-positive neurons. In the developing mouse brain, expression of Chd8 peaks from E16 to E18 and then decreases significantly at P14 to adulthood. Knockdown of Chd8 results in reduced axon and dendritic growth, disruption of axon projections to the contralateral cortex, and delayed neuronal migration at E18.5 which recovers by P3 and P7. Conclusion:Our findings indicate an important role for CHD8 in dendritic and axon development and neuronal migration and thus offer novel insights to further dissect the underlying molecular and circuit mechanisms of ASD caused by CHD8 deficiency.

SUBMITTER: Xu Q

PROVIDER: S-EPMC6299922 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons.

Xu Qiong Q Liu Yuan-Yuan YY Wang Xiaoming X Tan Guo-He GH Li Hui-Ping HP Hulbert Samuel W SW Li Chun-Yang CY Hu Chun-Chun CC Xiong Zhi-Qi ZQ Xu Xiu X Jiang Yong-Hui YH

Molecular autism 20181219

<h4>Background</h4>Mutations in <i>CHD8</i>, chromodomain helicase DNA-binding protein 8, are among the most replicated and common findings in genetic studies of autism spectrum disorder (ASD). The CHD8 protein is believed to act as a transcriptional regulator by remodeling chromatin structure and recruiting histone H1 to target genes. The mechanism by which deficiency of CHD8 causes ASD has not been fully elucidated.<h4>Methods</h4>We examined the expression of <i>CHD8</i> in human and mouse br ...[more]

PMID: 30574290

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Project description:BackgroundCHD8 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.MethodsTo 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.ResultsMild 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.ConclusionsTogether, 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.

Dataset Information

Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons.

Publications

Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons.

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