Arhgef2 regulates neural differentiation in the cerebral cortex through mRNA m6A-methylation of Npdc1 and Cend1

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. [Display omitted] •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