Germline Chd8 haploinsufficiency alters brain development in mouse

Nat Neurosci. 2017 Aug;20(8):1062-1073. doi: 10.1038/nn.4592. Epub 2017 Jun 26.

Abstract

The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8+/del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8+/del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8+/del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8+/del5 mice. This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.

MeSH terms

  • Animals
  • Brain / metabolism
  • Cell Cycle Proteins / genetics
  • Chromatin / metabolism
  • DNA-Binding Proteins / genetics*
  • Gene Expression Regulation, Developmental / genetics*
  • Gene Regulatory Networks / genetics*
  • Haploinsufficiency / genetics*
  • Mice, Transgenic
  • Mutation / genetics
  • Phenotype
  • Transcription Factors / genetics

Substances

  • Cell Cycle Proteins
  • Chromatin
  • DNA-Binding Proteins
  • Transcription Factors
  • duplin protein, mouse