文章基本信息

标题：Arhgef2 regulates neural differentiation in the cerebral cortex through mRNA m 6A-methylation of Npdc1 and Cend1
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作者：Pei Zhou ; Yifei Qi ; Xiang Fang 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：6
页码：1-21
DOI：10.1016/j.isci.2021.102645
语种：English
出版社：Elsevier
摘要：SummaryN6-methyladenosine (m6A) is emerging as a vital factor regulating neural differentiation. Here, we report that deficiency ofArhgef2, a novel cause of a neurodevelopmental disorder we identified recently, impairs neurogenesis, neurite outgrowth, and synaptic formation by regulating m6A methylation.Arhgef2knockout decreases expression ofMettl14and total m6A level significantly in the cerebral cortex. m6A sequencing reveals that loss ofArhgef2reduces m6A methylation of 1,622 mRNAs, includingNpdc1andCend1,which are both strongly associated with cell cycle exit and terminal neural differentiation.Arhgef2deficiency decreases m6A methylations of theNpdc1andCend1mRNAs via down-regulation of Mettl14, and thereby inhibits the translation ofNpdc1and nuclear export ofCend1mRNAs. Overexpression of Mettl14, Npdc1, and Cend1 rescue the abnormal phenotypes inArhgef2knockout mice, respectively. Our study provides a critical insight into a mechanism by which defectiveArhgef2mediates m6A-tagged target mRNAs to impair neural differentiation.Graphical abstractDisplay OmittedHighlights•Arhgef2 mediates total m6A level via Mettl14•Arhgef2affects m6A methylations of theNpdc1andCend1mRNAs•Decreased m6A methylations inhibits translation of Npdc1 and nuclear export of Cend1•Reduced protein expression of Npdc1 and Cend1 hinders neural differentiationMolecular neuroscience; Developmental neuroscience; Cellular neuroscience