http://purl.uniprot.org/citations/33023670 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/33023670 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
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http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/author | "Zylka M.J."xsd:string |
http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/author | "Schmid R.S."xsd:string |
http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/author | "Moy S.S."xsd:string |
http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/author | "Jimenez J.A."xsd:string |
http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/author | "Simon J.M."xsd:string |
http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/author | "Tuttle A.H."xsd:string |
http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/author | "Ptacek T.S."xsd:string |
http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/date | "2020"xsd:gYear |
http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/name | "Mol Autism"xsd:string |
http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/pages | "74"xsd:string |
http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/title | "Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life."xsd:string |
http://purl.uniprot.org/citations/33023670 | http://purl.uniprot.org/core/volume | "11"xsd:string |
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