Butler Tjaden Naomi E, Shannon Stephen R, Seidel Christopher W, Childers Melissa, Aoto Kazushi, Sandell Lisa L, Trainor Paul A
Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
bioRxiv. 2025 Jan 23:2025.01.23.634504. doi: 10.1101/2025.01.23.634504.
The enteric nervous system (ENS) is formed from vagal neural crest cells (NCC), which generate most of the neurons and glia that regulate gastrointestinal function. Defects in the migration or differentiation of NCC in the gut can result in gastrointestinal disorders such as Hirschsprung disease (HSCR). Although mutations in many genes have been associated with the etiology of HSCR, a significant proportion of affected individuals have an undetermined genetic diagnosis. Therefore, it's important to identify new genes, modifiers and environmental factors that regulate ENS development and disease. Rdh10 catalyzes the first oxidative step in the metabolism of vitamin A to its active metabolite, RA, and is therefore a central regulator of vitamin A metabolism and retinoic acid (RA) synthesis during embryogenesis. We discovered that () loss-of-function mouse embryos exhibit intestinal aganglionosis, characteristic of HSCR. Vagal NCC form and migrate in mutant embryos but fail to invade the foregut. is highly expressed in the mesenchyme surrounding the entrance to the foregut and is essential between E7.5-E9.5 for NCC invasion into the gut. Comparative RNA-sequencing revealed downregulation of the gene signaling network in mutants, which is critical for vagal NCC chemotaxis. Furthermore, the composition of the extracellular matrix through which NCC migrate is also altered, in part by increased collagen deposition. Collectively this restricts NCC entry into the gut, demonstrating that -mediated vitamin A metabolism and RA signaling pleiotropically regulates the NCC microenvironment during ENS formation and in the pathogenesis of intestinal aganglionosis.
肠神经系统（ENS）由迷走神经嵴细胞（NCC）形成，这些细胞产生大部分调节胃肠功能的神经元和神经胶质细胞。肠道中NCC迁移或分化的缺陷可导致诸如先天性巨结肠病（HSCR）等胃肠疾病。尽管许多基因的突变与HSCR的病因有关，但相当一部分受影响个体的基因诊断仍未确定。因此，识别调节ENS发育和疾病的新基因、修饰因子和环境因素很重要。Rdh10催化维生素A代谢为其活性代谢物视黄酸（RA）的第一步氧化反应，因此是胚胎发育过程中维生素A代谢和视黄酸（RA）合成的核心调节因子。我们发现，功能丧失的小鼠胚胎表现出肠道神经节缺失，这是HSCR的特征。迷走NCC在突变胚胎中形成并迁移，但未能侵入前肠。Rdh10在前肠入口周围的间充质中高度表达，在E7.5 - E9.5期间对于NCC侵入肠道至关重要。比较RNA测序揭示了突变体中Rdh10基因信号网络的下调，这对迷走NCC趋化性至关重要。此外，NCC迁移通过的细胞外基质的组成也发生了改变，部分原因是胶原蛋白沉积增加。总体而言，这限制了NCC进入肠道，表明Rdh10介导的维生素A代谢和RA信号传导在ENS形成过程中以及肠道神经节缺失的发病机制中多效性地调节NCC微环境。
