Arhgef2 regulates neural differentiation in the cerebral cortex through mRNA m6A-methylation of Npdc1 and Cend1
Pei Zhou, Yifei Qi, Xiang Fang, Miaomiao Yang, Shuxin Zheng, Caihua Liao, Fengying Qin, Lili Liu, Hong Li, Yan Li, Ethiraj Ravindran, Chuanbo Sun, Xinshu Wei, Wen Wang, Liang Fang, Dingding Han, Changgeng Peng, Wei Chen, Na Li, Angela M. Kaindl, Hao Hu
Abstract
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.