ASH1L is Necessary for Normal Development of Upper Layer Cortical Neurons
Abstract
Over 100 genes have been implicated in the genetic etiology of autism spectrum disorder (ASD). Many high confidence ASD genes are involved in chromatin remodeling, histone modifications and DNA methylation. Among these is ASH1L (Absent, Small, Homeotic-Like 1), which catalyzes histone H3K36 methylation and has a role in activating transcription by counteracting Polycomb repression. Over 130 autistic individuals have heterozygous loss-of-function ASH1L variants, and population studies confirm it is a high-risk autism gene. Several studies report autism-like behaviors in Ash1l deficient mice and characterized aspects of the underlying neuropathophysiology. However, the underlying genetic aberrations caused by Ash1l loss-of-function are poorly understood in the context of cortical development. We used mice with a cre-inducible deletion of Ash1l exon 4, which results in a frame shift and premature stop codon (p.V1693Afs*2). Firstly, we assessed the impact of global Ash1l loss-of-function on survival and craniofacial skeletal development. The proportion of homozygous Ash1l germline knockout embryos was normal at e18.5, however no live Ash1l null pups were present at birth (e18.5: n = 77, P = 0.90; p0: Ash1l+/+ n = 41, P = 0.00095). Ash1l-/- had shortened nasal bones at e18.5 (n = 31, P = 0.017) compared to heterozygous and wildtype littermates. To assess Ash1l loss-of-function specifically in the cortex, we used a tamoxifen-inducible cre strain to knockout Ash1l early in cortical…
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Evidence Hub reads this as a thesis, done in animal, not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health. Reported size: 130 participants or records.
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