Germline Chd8 haploinsufficiency alters brain development in mouse

被引：172

作者：

Gompers, Andrea L. ^{[1
,2
]}

Su-Feher, Linda ^{[1
,2
]}

Ellegood, Jacob ^{[3
]}

Copping, Nycole A. ^{[1
,4
]}

Riyadh, M. Asrafuzzaman ^{[5
]}

Stradleigh, Tyler W. ^{[1
,2
]}

Pride, Michael C. ^{[1
,4
]}

Schaffler, Melanie D. ^{[1
,4
]}

Wade, A. Ayanna ^{[1
,2
]}

Catta-Preta, Rinaldo ^{[1
,2
]}

Zdilar, Iva ^{[1
,2
]}

Louis, Shreya ^{[1
,2
]}

Kaushik, Gaurav ^{[5
]}

Mannion, Brandon J. ^{[6
]}

Plajzer-Frick, Ingrid ^{[6
]}

Afzal, Veena ^{[6
]}

Visel, Axel ^{[6
,7
,8
]}

Pennacchio, Len A. ^{[6
,7
]}

Dickel, Diane E. ^{[6
]}

Lerch, Jason P. ^{[3
,9
]}

Crawley, Jacqueline N. ^{[1
,4
]}

Zarbalis, Konstantinos S. ^{[5
]}

Silverman, Jill L. ^{[1
,4
]}

Nord, Alex S. ^{[1
,2
]}

机构：

[1] Univ Calif Davis, Dept Psychiat & Behav Sci, Davis, CA 95616 USA

[2] Univ Calif Davis, Dept Neurobiol Physiol & Behav, Davis, CA 95616 USA

[3] Hosp Sick Children, Mouse Imaging Ctr, Toronto, ON, Canada

[4] Univ Calif Davis, MIND Inst, Sch Med, Davis, CA 95616 USA

[5] Univ Calif Davis, Dept Pathol & Lab Med, Shriners Hosp Children, Inst Pediat Regenerat Med, Sacramento, CA 95817 USA

[6] Lawrence Berkeley Natl Lab, Funct Genom Dept, Berkeley, CA USA

[7] Joint Genome Inst, Dept Energy, Walnut Creek, CA USA

[8] Univ Calif Merced, Sch Nat Sci, Merced, CA USA

[9] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

来源：

NATURE NEUROSCIENCE | 2017年 / 20卷 / 08期

基金：

美国国家卫生研究院;

关键词：

AUTISM SPECTRUM DISORDER; CORTICAL NEUROGENESIS; MICE; MODELS; IMAGE; EXPRESSION; PROJECTION; MUTATIONS; PHENOTYPE; REGISTRATION;

D O I：

10.1038/nn.4592

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：1062 / +

页数：18

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