Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, Illkirch, France.
Life Sci Alliance. 2022 Nov 14;6(1). doi: 10.26508/lsa.202201456. Print 2023 Jan.
Individuals with mutations in present with gastrointestinal complaints, yet the underlying mechanisms are understudied. Here, using a stable constitutive mutant zebrafish model, we found that the loss of leads 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 of Furthermore, transcriptomic analyses revealed an altered expression of key receptors and enzymes in serotonin and acetylcholine signaling pathways. The tissue examination of mutants 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 between , NCC development, intestinal homeostasis, and autism-associated gastrointestinal complaints.
个体携带 基因突变时会出现胃肠道不适，但相关的潜在机制仍研究不足。在这里，我们利用一种稳定组成型激活的 突变斑马鱼模型发现，缺失 会导致迷走神经嵴细胞（NCC）、肠神经和神经胶质前体细胞数量减少，这些细胞从神经管中迁移出来，并且它们的早期迁移能力发生了改变。在后期阶段，尽管 NCC 完全定植于肠道，但我们发现产生血清素的肠嗜铬细胞和 NCC 衍生的 5-羟色胺能神经元数量减少，提示在没有 的情况下肠道中 5-羟色胺水平降低。此外，转录组分析显示，在 5-羟色胺和乙酰胆碱信号通路中关键受体和酶的表达发生改变。对 突变体的组织检查显示，肠道上皮层变薄，伴随着中性粒细胞的积累，杯状细胞和嗜酸性粒细胞数量减少。最后，对整个肠道的单细胞测序显示，免疫平衡被全面打乱，炎症细胞因子的表达失调，免疫细胞簇发生变化。我们的研究结果提出了一个因果关系，即 、NCC 发育、肠道稳态和自闭症相关的胃肠道不适之间存在发育上的联系。
