Loss of autism-candidate CHD8 perturbs neural crest development and intestinal homeostatic balance

Abstract

Individuals with mutations inCHD8present with gastrointestinal complaints, yet the underlying mechanisms are understudied. Here, using a stable constitutivechd8mutant zebrafish model, we found that the loss ofchd8leads to a reduced number of vagal neural crest cells (NCCs), enteric neural and glial progenitors, emigrating from the neural tube, and that their early migration capability was altered. At later stages, although the intestinal colonization by NCCs was complete, we found the decreased numbers of both serotonin-producing enterochromaffin cells and NCC-derived serotonergic neurons, suggesting an intestinal hyposerotonemia in the absence ofchd8. Furthermore, transcriptomic analyses revealed an altered expression of key receptors and enzymes in serotonin and acetylcholine signaling pathways. The tissue examination ofchd8mutants revealed a thinner intestinal epithelium accompanied by an accumulation of neutrophils and the decreased numbers of goblet cells and eosinophils. Last, single-cell sequencing of whole intestines showed a global disruption of the immune balance with a perturbed expression of inflammatory interleukins and changes in immune cell clusters. Our findings propose a causal developmental link betweenchd8, NCC development, intestinal homeostasis, and autism-associated gastrointestinal complaints.

Age-differential sexual dimorphisms in CHD8-S62X-mutant mouse synapses and transcriptomes

“…Previous studies on Chd8 -mutant mice and human neurons suggested multiple mechanisms that may underlie CHD8-related brain deficits ( Sugathan et al, 2014 ; Cotney et al, 2015 ; Wang et al, 2015 ; Breuss and Gleeson, 2016 ; Durak et al, 2016 ; Katayama et al, 2016 ; Gompers et al, 2017 ; Platt et al, 2017 ; Wang et al, 2017 ; Andreae and Basson, 2018 ; Jung et al, 2018 ; Suetterlin et al, 2018 ; Wade et al, 2018 ; Xu et al, 2018 ; Zhao et al, 2018 ; Hulbert et al, 2020 ; Jimenez et al, 2020 ; Sood et al, 2020 ; Cherepanov et al, 2021 ; Ding et al, 2021 ; Ellingford et al, 2021 ; Hurley et al, 2021 ; Kawamura et al, 2021 ; Kweon et al, 2021 ; Weissberg and Elliott, 2021 ; Chen et al, 2022 ; Coakley-Youngs et al, 2022 ; Dong et al, 2022 ; Haddad Derafshi et al, 2022 ; Jimenez et al, 2022 ; Kerschbamer et al, 2022 ; Lee et al, 2022 ; Paulsen et al, 2022 ; Thudium et al, 2022 ; Tu et al, 2022 ; Villa et al, 2022 ; Yu et al, 2022 ; Hayot et al, 2023 ). However, mechanisms underlying the male–female differences in CHD8-related ASD are poorly understood ( Jung et al, 2018 ; Cherepanov et al, 2021 ; Yu et al, 2022 ).…”

Gastrointestinal Dysfunction in Genetically Defined Neurodevelopmental Disorders

“…74 75 Various animal models of monogenic forms of ASD have displayed disruptions to these muscular contractions. 43 76 77 78 79 In a clinical ASD population, any of these disruptions could alter GI transit, impairing food bolus and thus nutrient absorption, potentially resulting in increased hospitalization, malnutrition, and emergency department visits. 43 76 77 78 79 80…”

“…74,75 Various animal models of monogenic forms of ASD have displayed disruptions to these muscular contractions. 43,[76][77][78][79] In a clinical ASD population, any of these disruptions could alter GI transit, impairing food bolus and thus nutrient absorption, potentially resulting in increased hospitalization, malnutrition, and emergency department visits. 43,[76][77][78][79][80] An NIH study by Witmer et al was one of few studies using both patient-reported outcome measures (PROMs), such as ROME IV criteria, and diagnostic testing in patients specifically with PMDS.…”

“…43,[76][77][78][79] In a clinical ASD population, any of these disruptions could alter GI transit, impairing food bolus and thus nutrient absorption, potentially resulting in increased hospitalization, malnutrition, and emergency department visits. 43,[76][77][78][79][80] An NIH study by Witmer et al was one of few studies using both patient-reported outcome measures (PROMs), such as ROME IV criteria, and diagnostic testing in patients specifically with PMDS. 51 Transit time in the colon was measured by colonic manometry (invasive and performed via colonoscopic placement) and a radiopaque marker study.…”

Meeting report: Third Franco‐Japanese developmental biology meeting “New Frontiers in developmental biology: Celebrating the diversity of life”

“…The next session was "Regeneration & stem cells, aging, senescence." In this session, six speakers showed their results regarding the dynamics of gene expression in stem and progenitors cells from various tissues, such as during ectomesenchyme specification (Zalc et al, 2021) (Antoine Zalc, Cochin Institute), homeostasis of the intestine (Hayot, Massonot, Keime, Faure, & Golzio, 2023) (Mathieu Massonot, IGBMC Strasbourg), regeneration of the fin in zebrafish (Cudak, Lopez-Delgado, Keil, & Knopf, 2023) (Franziska Knopf, Center for Regenerative Therapies TU Dresden & Center for Healthy Aging, Medical Faculty TU Dresden) and aging process (Aiko Sada, Kumamoto University). Thereby illustrating beautifully how we need to expand our understanding of cell differentiation potential.…”