Loss of autism-candidate CHD8 perturbs neural crest development and intestinal homeostatic balance [scRNA-seq]

ABSTRACT: Individuals with mutations in CHD8 present with gastrointestinal complaints, yet the underlying mechanisms are understudied. Here, utilizing a stable constitutive chd8 mutant zebrafish model, we found that the loss of chd8 leads to 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 the NCCs was complete, we found decreased numbers of both serotonin-producing enterochromaffin cells and NCC-derived serotonergic neurons, suggesting an intestinal hyposerotonemia in absence of chd8. Further, transcriptomic analyses revealed altered expression of key receptors and enzymes in serotonin and acetylcholine signaling pathways. Tissue examination of chd8 mutants revealed thinner intestinal epithelium accompanied by accumulation of neutrophils and decreased numbers of goblet cells and eosinophils. Last, single-cell sequencing of whole intestines showed a global disruption of the immune balance with perturbed expression of inflammatory interleukins and changes in immune cell clusters. Our findings propose a causal developmental link between chd8, NCC development, intestinal homeostasis, and autism-associated gastrointestinal complaints.

ORGANISM(S): Danio rerio

PROVIDER: GSE184363 | GEO | 2022/10/21

REPOSITORIES: GEO