Department of Physiology & Membrane Biology, Shriners Hospitals for Children Northern California, University of California Davis, School of Medicine, Sacramento, CA, 95817, USA.
Tufts-USDA Human Nutrition Research Center on Aging, Boston, MA, USA.
Nat Commun. 2024 Feb 22;15(1):1642. doi: 10.1038/s41467-024-45775-1.
Folate supplementation reduces the occurrence of neural tube defects (NTDs), birth defects consisting in the failure of the neural tube to form and close. The mechanisms underlying NTDs and their prevention by folate remain unclear. Here we show that folate receptor 1 (FOLR1) is necessary for the formation of neural tube-like structures in human-cell derived neural organoids. FOLR1 knockdown in neural organoids and in Xenopus laevis embryos leads to NTDs that are rescued by pteroate, a folate precursor that is unable to participate in metabolism. We demonstrate that FOLR1 interacts with and opposes the function of CD2-associated protein, molecule essential for apical endocytosis and turnover of C-cadherin in neural plate cells. In addition, folates increase Ca transient frequency, suggesting that folate and FOLR1 signal intracellularly to regulate neural plate folding. This study identifies a mechanism of action of folate distinct from its vitamin function during neural tube formation.
叶酸补充可减少神经管缺陷（NTDs）的发生，NTDs 是指神经管未能形成和闭合的出生缺陷。NTDs 的发生机制及其叶酸预防作用仍不清楚。本研究表明，叶酸受体 1（FOLR1）是人类细胞衍生的神经类器官中形成神经管样结构所必需的。FOLR1 在神经类器官和非洲爪蟾胚胎中的敲低导致 NTDs，而蝶酰谷氨酸（一种不能参与代谢的叶酸前体）可以挽救这些缺陷。我们证明 FOLR1 与 CD2 相关蛋白相互作用并拮抗其功能，后者是神经板细胞中顶质内吞作用和 C-钙粘蛋白周转所必需的分子。此外，叶酸增加钙瞬变频率，提示叶酸和 FOLR1 通过信号转导在细胞内调节神经板折叠。这项研究确定了叶酸在神经管形成过程中的作用机制，不同于其维生素功能。
