The autism-associated protein CHD8 is required for cerebellar development and motor function

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Mutations in chromodomain helicase DNA-binding protein 8 (CHD8) are strongly associated with autism spectrum disorder (ASD).
• The cerebellum's role in ASD pathogenesis is debated, with limited understanding of CHD8's function in this brain region.

Purpose of the Study:

• To investigate the role of CHD8 in cerebellar development and its contribution to ASD phenotypes.
• To determine if CHD8 dysfunction in cerebellar granule neuron progenitors (GNPs) affects their proliferation, differentiation, and overall cerebellar structure.

Main Methods:

• Generation of a mouse model with cerebellum-specific deletion of the Chd8 gene in GNPs.
• Analysis of GNP proliferation and differentiation, cerebellar morphology, motor coordination, and ASD-like behaviors.
• Chromatin immunoprecipitation sequencing (ChIP-seq) to assess CHD8 binding and chromatin accessibility.

Main Results:

• Cerebellar deletion of Chd8 impaired GNP proliferation and differentiation, leading to cerebellar hypoplasia and motor coordination deficits in mice.
• No ASD-like behavioral abnormalities were observed in mice with cerebellar Chd8 deletion.
• CHD8 was found to regulate neuronal gene expression in GNPs by binding to promoter regions and modulating chromatin accessibility.

Conclusions:

• CHD8 plays a critical role in cerebellar development, specifically in the proliferation and differentiation of GNPs.
• While cerebellar CHD8 dysfunction affects motor coordination, it does not appear to be the primary driver of ASD-like behaviors.
• These findings highlight the cerebellum's contribution to neurodevelopmental disorders and the complex etiology of ASD.