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

Germline Chd8 haploinsufficiency alters brain development in mouse.

Author information

1
Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, California, USA.
2
Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, California, USA.
3
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
4
MIND Institute, School of Medicine, University of California, Davis, Davis, California, USA.
5
Department of Pathology and Laboratory Medicine, Shriners Hospitals for Children, Institute for Pediatric Regenerative Medicine, University of California, Davis, Sacramento, California, USA.
6
Lawrence Berkeley National Laboratory, Functional Genomics Department, Berkeley, California, USA.
7
Department of Energy Joint Genome Institute, Walnut Creek, California, USA.
8
School of Natural Sciences, University of California, Merced, California, USA.
9
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

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.

PMID:
28671691
PMCID:
PMC6008102
DOI:
10.1038/nn.4592
[Indexed for MEDLINE]
Free PMC Article

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