Affiliation:
1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
2. Centre National de la Recherche Scientifique, Illkirch, France
3. Institut National de la Santé et de la Recherche Médicale, Illkirch, France
4. Université de Strasbourg, Strasbourg, France
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.
Funder
Agence Nationale de la Recherche
IdEx Unistra
SFRI-STRAT’US project
EUR IMCBio
Publisher
Life Science Alliance, LLC
Subject
Health, Toxicology and Mutagenesis,Plant Science,Biochemistry, Genetics and Molecular Biology (miscellaneous),Ecology
Cited by
8 articles.
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