Arhgef2 regulates neural differentiation in the cerebral cortex through mRNA m(6)A-methylation of Npdc1 and Cend1.
Arhgef2 regulates neural differentiation in the cerebral cortex through mRNA m(6)A-methylation of Npdc1 and Cend1.
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DOI：
10.1016/j.isci.2021.102645
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发表时间：
2021-06-25
期刊：
影响因子：
5.8
通讯作者：
Hu H
中科院分区：
文献类型：
--
作者：
Zhou P;Qi Y;Fang X;Yang M;Zheng S;Liao C;Qin F;Liu L;Li H;Li Y;Ravindran E;Sun C;Wei X;Wang W;Fang L;Han D;Peng C;Chen W;Li N;Kaindl AM;Hu H
N6-甲基腺苷（m6 A）正在成为调节神经分化的重要因素。在这里，我们报告说，缺乏Arhgef 2，一个新的原因，我们最近发现的神经发育障碍，损害神经发生，轴突生长，和突触形成通过调节m6 A甲基化。Arhgef 2基因敲除可显著降低大脑皮层Mettl 14的表达和总m6 A水平。m6 A测序显示，Arhgef 2的缺失减少了1，622种mRNAs的m6 A甲基化，包括Npdc 1和Cend 1，这两者都与细胞周期退出和终末神经分化密切相关。Arhgef 2缺陷通过下调Mettl 14降低Npdc 1和Cend 1 mRNA的m6 A甲基化，从而抑制Npdc 1的翻译和Cend 1 mRNA的核输出。Mettl 14、Npdc 1和Cend 1的过表达分别挽救了Arhgef 2敲除小鼠中的异常表型。我们的研究提供了一个关键的洞察机制，缺陷Arhgef 2介导m6 A标记的靶mRNA损害神经分化。Arhgef 2通过Mettl 14介导总m6 A水平Arhgef 2影响Npdc 1和Cend 1 mRNA的m6 A甲基化降低的m6 A甲基化抑制Npdc 1的翻译和Cend 1的核输出降低的Npdc 1和Cend 1的蛋白表达阻碍神经分化分子神经科学;发育神经科学;细胞神经科学
N6-methyladenosine (m6A) is emerging as a vital factor regulating neural differentiation. Here, we report that deficiency of Arhgef2, a novel cause of a neurodevelopmental disorder we identified recently, impairs neurogenesis, neurite outgrowth, and synaptic formation by regulating m6A methylation. Arhgef2 knockout decreases expression of Mettl14 and total m6A level significantly in the cerebral cortex. m6A sequencing reveals that loss of Arhgef2 reduces m6A methylation of 1,622 mRNAs, including Npdc1 and Cend1, which are both strongly associated with cell cycle exit and terminal neural differentiation. Arhgef2 deficiency decreases m6A methylations of the Npdc1 and Cend1 mRNAs via down-regulation of Mettl14, and thereby inhibits the translation of Npdc1 and nuclear export of Cend1 mRNAs. Overexpression of Mettl14, Npdc1, and Cend1 rescue the abnormal phenotypes in Arhgef2 knockout mice, respectively. Our study provides a critical insight into a mechanism by which defective Arhgef2 mediates m6A-tagged target mRNAs to impair neural differentiation. Arhgef2 mediates total m6A level via Mettl14 Arhgef2 affects m6A methylations of the Npdc1 and Cend1 mRNAs Decreased m6A methylations inhibits translation of Npdc1 and nuclear export of Cend1 Reduced protein expression of Npdc1 and Cend1 hinders neural differentiation Molecular neuroscience; Developmental neuroscience; Cellular neuroscience
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