Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA.
Development. 2010 Feb;137(4):631-40. doi: 10.1242/dev.040550.
Hirschsprung disease is a serious disorder of enteric nervous system (ENS) development caused by the failure of ENS precursor migration into the distal bowel. We now demonstrate that retinoic acid (RA) is crucial for GDNF-induced ENS precursor migration, cell polarization and lamellipodia formation, and that vitamin A depletion causes distal bowel aganglionosis in serum retinol-binding-protein-deficient (Rbp4(-/-)) mice. Ret heterozygosity increases the incidence and severity of distal bowel aganglionosis induced by vitamin A deficiency in Rbp4(-/-) animals. Furthermore, RA reduces phosphatase and tensin homolog (Pten) accumulation in migrating cells, whereas Pten overexpression slows ENS precursor migration. Collectively, these data support the hypothesis that vitamin A deficiency is a non-genetic risk factor that increases Hirschsprung disease penetrance and expressivity, suggesting that some cases of Hirschsprung disease might be preventable by optimizing maternal nutrition.
先天性巨结肠是一种严重的肠神经系统（ENS）发育障碍，是由于 ENS 前体细胞未能迁移到远端肠道而引起的。我们现在证明，视黄酸（RA）对于 GDNF 诱导的 ENS 前体细胞迁移、细胞极化和片状伪足形成至关重要，并且维生素 A 耗竭会导致血清视黄醇结合蛋白缺陷（Rbp4（-/-））小鼠的远端肠道无神经节。Ret 杂合性增加了维生素 A 缺乏在 Rbp4（-/-）动物中诱导的远端肠道无神经节的发生率和严重程度。此外，RA 减少了迁移细胞中磷酸酶和张力蛋白同源物（Pten）的积累，而 Pten 的过表达则减缓了 ENS 前体细胞的迁移。总之，这些数据支持了维生素 A 缺乏是增加先天性巨结肠病外显率和表现度的非遗传风险因素的假设，表明某些先天性巨结肠病病例可能可以通过优化母体营养来预防。
