Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life

Molecular Autism

Sheryl S. Moy¹  Jessica A. Jiménez²  Ralf S. Schmid³  Alex H. Tuttle⁴  Travis S. Ptacek⁴  Mark J. Zylka⁵  Jeremy M. Simon⁶ 

[1] Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;Department of Psychiatry, The University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;Curriculum in Toxicology & Environmental Medicine, The University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;UNC Neuroscience Center, The University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;UNC Neuroscience Center, The University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;UNC Neuroscience Center, The University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;UNC Neuroscience Center, The University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;Department of Genetics, The University of North Carolina at Chapel Hill, Campus Box #7264, 27599, Chapel Hill, NC, USA;

关键词: CHD8;    Macrocephaly;    Brain overgrowth;    Autism spectrum disorder;    Unfolded protein response;    Endoplasmic reticulum stress;   

DOI  :  10.1186/s13229-020-00369-8

来源: Springer

【 摘 要 】

BackgroundChromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown.MethodsWe generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months).ResultsChd8V986*/+ mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8V986*/+ mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8V986*/+ crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8V986*/+ mice and then equalized relative to wild-type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8V986*/+ mice, whereas genes associated with the c-MET signaling pathway were increased in expression.LimitationsIt is unclear whether the transcriptional changes observed with age in Chd8V986*/+ mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities.ConclusionsCollectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8V986*/+ mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8V986*/+ mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice.

【 授权许可】

CC BY