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

N ⁶-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.