Mettl3-mediated m6 A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant-like effects.

Abstract

N6 -methyladenosine (m6 A) is the most abundant mRNA modification affecting diverse biological processes. However, the functions and precise mechanisms of m6 A signaling in adult hippocampal neurogenesis and neurogenesis-related depression remain largely enigmatic. We found that depletion of Mettl3 or Mettl14 in neural stem cells (NSCs) dramatically reduced m6 A abundance, proliferation, and neuronal genesis, coupled with enhanced glial differentiation. Conversely, overexpressing Mettl3 promoted proliferation and neuronal differentiation. Mechanistically, the m6 A modification of Lrp2mRNA by Mettl3 enhanced its stability and translation efficiency relying on the reader protein Ythdc2, which in turn promoted neurogenesis. Importantly, mice lacking Mettl3manifested reduced hippocampalneurogenesis, which could contribute to spatial memory decline, and depression-like behaviors. We found that these defective behaviors were notably reversed by Lrp2 overexpression. Moreover, Mettl3 overexpression in the hippocampus of depressive mice rescues behavioral defects. Our findings uncover the biological role of m6 A modification in Lrp2-mediated neurogenesis via m6 A-binding protein Ythdc2, andproposearationale that targeting Mettl3-Ythdc2-Lrp2 axis regulation of neurogenesis might serve as a promising antidepressant strategy.