mA demethylase Alkbh3 regulates neurogenesis through mA demethylation of Mmp15 mRNA.

Background: N-Methyladenosine (mA) is an abundant modification of transcripts regulating mRNA structure and translation efficiency. However, the characteristics and biological functions of mRNA mA modification in adult hippocampal neurogenesis remain enigmatic.

Results: We found that mA demethylase Alkbh3 was dramatically enriched in neurons and neuronal genesis. Functionally, depletion of Alkbh3 in neural stem cells (NSCs) significantly decreased mA modification, neuronal differentiation and proliferation coupling with increasing gliogenesis, whereas overexpressing Alkbh3 facilitated neuronal differentiation and proliferation. Mechanistically, the mA demethylation of Mmp15 mRNA by Alkbh3 improved its RNA stability and translational efficacy, which promoted neurogenesis. Therapeutically, the silencing of Alkbh3 reduced hippocampal neurogenesis and impaired spatial memory in the adult mice.

Conclusions: We reveal a novel function of mA demethylation on Mmp15 mRNA in Alkbh3-mediated neurogenesis, which shed light on advancing Alkbh3 regulation of neurogenesis as a novel neurotherapeutic strategy.