Research Center of Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Ba-Da-Chu Road, Beijing, 100144, People's Republic of China.
Int J Biol Sci. 2020 Jan 1;16(1):85-98. doi: 10.7150/ijbs.33976. eCollection 2020.
Folate deficiency has long been associated with the abnormal development of the neural crest cells (NCCs) and neural tube defects (NTDs). RNA binding proteins (RBPs) also play important roles in the normal neural crest development and neural tube formation. Nevertheless, the causative mechanism by which folate status influences human NCCs development and the RBPs functions remains unknown. In this study, we differentiated H9 human embryonic stem cells into neural crest cells (H9-NCCs) and then constructed three folic acid (FA) deficiency (FAD) H9-NCCs models . Decreased viability, impaired migration and promoted apoptosis of H9-NCCs were observed in three FAD H9-NCCs models. In addition, we showed that three RBPs, namely, , and were up-regulated both in the FAD H9-NCC models and in the FAD mouse model . Knocking down of these three RBPs increased the H9-NCC viability and RCAN2 knockdown further promoted H9-NCC migration under FAD conditions. In normal culture condition, overexpression of RCAN2 and HnRNPC did not affect viabilities and migration of H9-NCCs while overexpression of LARP6 reduced the H9-NCC viability. Our findings demonstrate important regulatory effects of RBPs underlying FAD-induced impaired function of NCCs.
叶酸缺乏症一直与神经嵴细胞（NCCs）的异常发育和神经管缺陷（NTDs）有关。RNA 结合蛋白（RBPs）在正常神经嵴发育和神经管形成中也起着重要作用。然而，叶酸状态如何影响人类 NCCs 发育和 RBP 功能的因果机制尚不清楚。在这项研究中，我们将 H9 人胚胎干细胞分化为神经嵴细胞（H9-NCCs），然后构建了三种叶酸缺乏（FAD）的 H9-NCC 模型。在三种 FAD H9-NCC 模型中，H9-NCC 的活力降低，迁移受损，凋亡增加。此外，我们还表明，三种 RBP，即 、 和 ，在 FAD H9-NCC 模型和 FAD 小鼠模型中均上调。敲低这三种 RBP 可增加 H9-NCC 的活力，而在 FAD 条件下，RCAN2 敲低进一步促进了 H9-NCC 的迁移。在正常培养条件下，RCAN2 和 HnRNPC 的过表达并不影响 H9-NCC 的活力和迁移，而 LARP6 的过表达则降低了 H9-NCC 的活力。我们的研究结果表明，RBP 对 FAD 诱导的 NCC 功能障碍具有重要的调节作用。
