| First Author | Gompers AL | Year | 2017 |
| Journal | Nat Neurosci | Volume | 20 |
| Issue | 8 | Pages | 1062-1073 |
| PubMed ID | 28671691 | Mgi Jnum | J:249066 |
| Mgi Id | MGI:6093009 | Doi | 10.1038/nn.4592 |
| Citation | Gompers AL, et al. (2017) Germline Chd8 haploinsufficiency alters brain development in mouse. Nat Neurosci 20(8):1062-1073 |
| abstractText | 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. |
