Mettl3-Mediated M 6 a Modifcation of Lrp2 Facilitates Neurogenesis Through Ythdc2 and Elicits Antidepressant-Like Effects

Background: N6-methyladenosine (m6A) is the most abundant mRNA modification affecting diverse biological processes. However, the functions and precise mechanisms of m6A signaling in adult hippocampal neurogenesis and neurogenesis-related depression remain largely enigmatic. Methods: We profiled the dynamic Mettl3 or Mettl14 expressions and m6A modification during neuronal differentiation of neural stem cells (NSCs) in vitro and in vivo. Adult hippocampal neurogenesis and its molecular mechanisms were examined by morphology, biochemical methods and biological sequencing. The depression-like behaviors of the mice were assessed with the social interaction test, forced swimming test, tail suspension test and sucrose preference test. Findings: We found that depletion of Mettl3 or Mettl14 in NSCs dramatically reduced m6A abundance, proliferation and neuronal genesis, coupled with enhanced glial differentiation. Conversely, overexpressing Mettl3 promoted proliferation and neuronal differentiation. Mechanistically, Mettl3 and m6A reader Ythdc2 recognized m6A residues on Lrp2 3′-UTR and mediated its mRNA stability and translation, leading to the differentiation-promoting effects of Mettl3. Importantly, mice lacking Mettl3 manifested reduced hippocampal neurogenesis, which could contribute to spatial memory decline, and depression-like behaviors. The defective behaviors were notably reversed by Lrp2 overexpression. Moreover, Mettl3 overexpression in the hippocampus of depressive mice rescues behavioral defects. Interpretation: Our findings uncover the biological role of m6A modification in Lrp2-mediated neurogenesis via m6A-binding protein Ythdc2, and propose a rationale that targeting Mettl3-Ythdc2-Lrp2 axis regulation of neurogenesis might serve as a promising antidepressant strategy. Funding: This work was supported by the National Natural Science Foundation of China (81371217), Research Grant of Guangdong Province Key Laboratory of Psychiatric Disorders (N201901), Innovation and Strong College Program of Guangdong (2018KTSCX183), Natural Science Foundation of Guangdong (2017A030313520), Science and Technology Foundation of Guangzhou (201707010231). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: The experiment was carried out in accordance with the "Guidelines for the Protection and Use of Animals in China", and the experimental protocols were approved by the Animal Ethics Committee of Guangzhou Medical University.