Mouse Model of Chd8 Haploinsufficiency Results in Altered Neuronal Proliferation and Megalencephaly

Saturday, May 13, 2017: 12:00 PM-1:40 PM
Golden Gate Ballroom (Marriott Marquis Hotel)
A. Gompers1, L. Su-Feher2, J. Ellegood3, T. W. Stradleigh2, I. Zdilar2, N. A. Copping4, M. C. Pride4, M. A. Riyadh5, G. Kaushik6, J. P. Lerch7, B. Mannion8, V. Azal8, A. Visel8, L. A. Pennacchio8, D. Dickel8, J. Crawley9, K. Zarbalis10, J. L. Silverman11 and A. S. Nord2, (1)University of California, Davis, Davis, CA, (2)Center for Neuroscience, Department of Neurobiology, Physiology, & Behavior, University of California, Davis, Davis, CA, (3)Hospital for Sick Children, Toronto, ON, CANADA, (4)UC Davis, Sacramento, CA, (5)University of California-Davis, sacramento, CA, (6)University of California-Davis, Sacrameto, CA, (7)Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada, (8)Lawrence Berkley Laboratories, Berkley, CA, (9)University of California, Sacramento, CA, (10)University of California Davis, Davis, CA, (11)MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA
Background: Efforts to uncover the genetic basic of Autism Spectrum Disorder (ASD) via exome sequencing of autism patients have identified the chromodomain helicase binding protein (CHD8) as a candidate gene. Patients with de novo mutations in CHD8, resulting in loss of function and haploinsufficiency, show a clinical presentation of autism comorbid with cognitive impairment, macrocephaly, craniofacial dysmorphology, and gastrointestinal issues.

Objectives: To uncover neurodevelopmental pathology associated with CHD8 haploinsufficiency driving in autism, macrocephaly, and impaired cognition utilizing a mouse model

Methods: We generated a mouse model harboring a germline mutation in Chd8 using the CRISPR/Cas9 system. We performed RNA-sequencing across development to analyze changes in gene expression in Chd8 heterozygous (Chd8+/-) forebrain. We used EdU labeling to measure neuronal proliferation at embryonic day 13.5. We utilized a battery of behavioral tests to assess social, repetitive and cognitive behaviors in adult Chd8+/- mice.

Results: Consistent with previous publications, homozygous deletion of Chd8 in our mouse model is embryonic lethal. We found altered expression of early neurodevelopmental and differentiation genes in Chd8+/- forebrain, including sets of genes critical for RNA processing (including RNA splicing, mRNA stability, and transport) and chromatin structure and organization. Chd8+/- mice have increased neuronal proliferation in the ventricular zone at embryonic day 13.5, the peak of neurogenesis. We observed increased cortical length and cortical thickness at postnatal day 7. Cursory examination of cortical lamination revealed no obvious differences in layer specification in at postnatal day 1. Our behavioral assays did not reveal social or anxiety phenotypes in assays that have face value validity for autism. Preliminary analysis in a fear-based learning task suggested impaired cue and correlative learning in Chd8+/- mice.

Conclusions: Our mouse model recapitulates human macrocephaly phenotype, reveals elevated neuronal proliferation as a possible root for brain size increase, and provides insight into the gene expression networks altered by mutation of one copy of the Chd8 gene.