Germline Chd8 haploinsufficiency alters brain development in mouse

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• CHD8 is a key gene in neurodevelopmental gene networks linked to autism spectrum disorder.
• Germline heterozygous mutations in CHD8 are associated with neurodevelopmental disorders in humans.

Purpose of the Study:

• To investigate the impact of a heterozygous frameshift mutation in the Chd8 gene on mouse neurodevelopment.
• To characterize the molecular and phenotypic consequences of Chd8 haploinsufficiency in a mouse model.

Main Methods:

• Utilized a mouse model with a germline heterozygous frameshift mutation in Chd8 (Chd8+/del5).
• Conducted behavioral assessments for social interaction and repetitive behaviors.
• Performed network analysis of gene expression to identify transcriptional changes.
• Validated specific molecular alterations, including RNA processing and cell-cycle gene dysregulation.

Main Results:

• Chd8+/del5 mice showed cognitive impairment and increased regional brain volume, but no social or repetitive behavior deficits.
• Network analysis revealed widespread transcriptional changes in neurogenesis, synaptic processes, and neuroimmune signaling pathways.
• A specific co-expression module implicated in early brain development showed dysregulation of RNA processing, chromatin remodeling, and cell-cycle genes.
• Increased neuronal proliferation and aberrant developmental splicing were confirmed in Chd8+/del5 mice.

Conclusions:

• Chd8 haploinsufficiency in mice recapitulates key aspects of human CHD8 mutation pathology, including cognitive deficits and brain overgrowth.
• Widespread transcriptional dysregulation across critical neurodevelopmental pathways underlies the observed phenotypes.
• The findings highlight the role of Chd8 in regulating gene expression networks essential for normal brain development, including RNA processing and cell-cycle control.