PLX016855

GSE142208: Chd8 haploinsufficiency impairs early brain development and impacts protein homeostasis later in life

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Chromodomain helicase DNA-binding protein 8 (CHD8), now considered a master transcriptional regulator for autism, is mutated in more autism probands (0.45%) than any other gene. We generated mutant mice with a human loss-of-function (LOF) mutation in Chd8 (Val986X, henceforth referred to as V986*). Heterozygous mutant mice (Chd8V986*/+) display features of ASD, including anxiety like behavior and macrocephaly. Perturbation of CHD8 also recapitulates increased sociability found in other CHD8 mutant animal models. Our study expands previously identified knowledge of CHD8 mutant mouse models by examining temporal alterations in the transcriptional profile of mouse cortical tissue resulting from a reduction in CHD8 expression. Dysregulation of major cellular processes uniquely includes a reduction in neuronal signaling, focal adhesion, and synaptic function genes early in development, that increase in expression into adulthood. At 12 months, heterozygous mice display decreased endoplasmic reticulum (ER) stress, decreased unfolded protein response (UPR) and increased MET signaling likely resulting from a combination of reduced CHD8 expression and reflecting an altered network structure formed early in development. These data provide greater insight into the role of CHD8 in brain function and how mutations in the gene can contribute to ASD etiology. SOURCE: Travis Ptacek (tptacek@email.unc.edu) - UNC Neuroscience Center Bioinformatics Core