Up-regulation of RNA Binding Proteins Contributes to Folate Deficiency-Induced Neural Crest Cells Dysfunction
Up-regulation of RNA Binding Proteins Contributes to Folate Deficiency-Induced Neural Crest Cells Dysfunction
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DOI：
10.7150/ijbs.33976
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发表时间：
2020-01-01
影响因子：
9.2
通讯作者：
Xiao, Ran
中科院分区：
文献类型：
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作者：
Liu, Wenbo;Wang, Kang;Xiao, Ran
长期以来，叶酸缺乏与神经嵴细胞（NCC）和神经管缺陷（NTD）的异常发育有关。RNA结合蛋白（RBP）在神经嵴的正常发育和神经管的形成中也起着重要的作用。然而，叶酸状态影响人类NCC发展和RBP功能的致病机制仍然未知。本研究将H9人胚胎干细胞诱导分化为神经嵴细胞（H9-NCCs），并在体外构建了三种叶酸缺乏（FAD）的H9-NCCs模型。在三种FAD H9-NCC模型中观察到H9-NCC的活力降低、迁移受损和凋亡促进。此外，我们发现，三种RBP，即hnRNPC，LARP 6和RCAN 2，在体外FAD H9-NCC模型和体内FAD小鼠模型中均上调。敲低这三种RBP增加了H9-NCC活力，并且RCAN 2敲低进一步促进了FAD条件下H9-NCC迁移。在正常培养条件下，RCAN 2和HnRNPC的过表达不影响H9-NCC的活力和迁移，而LARP 6的过表达降低H9-NCC的活力。我们的研究结果表明，重要的调节作用的RBP基础FAD诱导的NCC功能受损。
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 in vitro. 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, hnRNPC, LARP6 and RCAN2, were up-regulated both in the FAD H9-NCC models in vitro and in the FAD mouse model in vivo. 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.