Mettl3‐mediated m⁶A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant‐like effects

Abstract

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. We found that depletion of Mettl3 or Mettl14 in neural stem cells (NSCs) dramatically reduced m6A abundance, proliferation, and neuronal genesis, coupled with enhanced glial differentiation. Conversely, overexpressing Mettl3 promoted proliferation and neuronal differentiation. Mechanistically, the m6A modification of Lrp2 mRNA by Mettl3 enhanced its stability and translation efficiency relying on the reader protein Ythdc2, which in turn promoted neurogenesis. Importantly, mice lacking Mettl3 manifested reduced hippocampal neurogenesis, 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 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.

The Regulatory Network of METTL3 in the Nervous System: Diagnostic Biomarkers and Therapeutic Targets

“…Consistently, depletion of METTL3 in mice also showed reduced hippocampal neurogenesis, decreased spatial memory, and depression-like behavior [ 20 ]. Overexpression of either METTL3 or Lrp2 in the hippocampus of depressed mice may rescue these behavioral deficits [ 20 ]. Collectively, these findings demonstrate that METTL3 modulates adult hippocampal neurogenesis by targeting the Ythdc2-Lrp2 axis ( Figure 2 ).…”

“…These findings indicate that METTL3-mediated m6A modification plays an important role in regulating neurogenesis and neuronal development by targeting Ezh2 [ 15 ]. In addition, in an adult hippocampal neurogenesis study, it was shown that the knock-down of METTL3 in NSCs dramatically reduced proliferation and neuronal genesis, while enhancing glial differentiation [ 20 ]. Mechanically, METTL3 enhances the stability and translation efficiency of Lrp2 mRNA by relying on the reader protein Ythdc2, which in turn promotes neurogenesis [ 20 ].…”

“…In addition, in an adult hippocampal neurogenesis study, it was shown that the knock-down of METTL3 in NSCs dramatically reduced proliferation and neuronal genesis, while enhancing glial differentiation [ 20 ]. Mechanically, METTL3 enhances the stability and translation efficiency of Lrp2 mRNA by relying on the reader protein Ythdc2, which in turn promotes neurogenesis [ 20 ]. Consistently, depletion of METTL3 in mice also showed reduced hippocampal neurogenesis, decreased spatial memory, and depression-like behavior [ 20 ].…”

“…Mechanically, METTL3 enhances the stability and translation efficiency of Lrp2 mRNA by relying on the reader protein Ythdc2, which in turn promotes neurogenesis [ 20 ]. Consistently, depletion of METTL3 in mice also showed reduced hippocampal neurogenesis, decreased spatial memory, and depression-like behavior [ 20 ]. Overexpression of either METTL3 or Lrp2 in the hippocampus of depressed mice may rescue these behavioral deficits [ 20 ].…”

Single cell discovery of m6A RNA modifications in the hippocampus

“…Interestingly, METTL3 depletion only in CAMK2A expressing cells in the mouse hippocampus was shown to reduce long-term memory consolidation, highlighting the functional and biological importance of these cells(Zhang et al 2018b). Also, reports have shown depression-like behavior, decreased spatial memory altered fear conditioning when the METTL3 m 6 A methylase is depleted in mice(Engel et al 2018; Xu et al 2022). Since these phenotypes are as well regulated by the hippocampus and by CAMK2A neurons, the absence of CAMK2A cells in our E-YTH single cell data but not in our E-YTH mut controls corroborates that the phenotypes associated with m 6 A deregulation are indeed due to abnormalities in m 6 A transcripts of CAMK2A expressing cells.…”