Abstract
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.
Highlights
Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD)
Chd8V986*/+ male and female mice were comparable in body weight at birth (P0) but displayed significantly increased brain weight when compared to WT littermate controls (Fig. 1d, e)
We found that genes associated with heat shock factor 1 (HSF1) signaling and chaperone function were reduced in 12-month-old Chd8V986*/+ samples
Summary
Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). Autism spectrum disorder (ASD) is characterized by social deficits and repetitive/restricted behaviors and affects approximately 0.6% of the global population [1]. Recent whole exome and whole genome sequencing studies identified various ASD risk alleles, but the underlying biology and disease progression associated with these mutations remain poorly understood [2,3,4,5,6]. Chromodomain helicase DNA-binding protein 8 (CHD8) encodes an ATP-dependent chromatin remodeler. Subsequent studies found that de novo heterozygous loss-of-function mutations in CHD8 are relatively common in ASD probands [4, 8,9,10,11,12]. Individuals with disruptive CHD8 mutations are disproportionately male (3.5:1) and present with shared symptoms, including macrocephaly, neonatal hypotonia, distinct facial features, and gastrointestinal problems [9, 13, 14]
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