Mettl3-mediated m6 A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant-like
Biao Xu1, Qingfeng Li1, Yuanfei Wu1
1Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
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 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 m6 A modification in Lrp2-mediated neurogenesis via m6 A-binding protein Ythdc2, and propose a rationale that targeting Mettl3-Ythdc2-Lrp2 axis regulation of neurogenesis might serve as a promising antidepressant strategy.
Insights
N6-methyladenosine (m6A) RNA modification regulates neural stem cell functions. Targeting the Mettl3-Ythdc2-Lrp2 pathway in the hippocampus shows promise for treating depression by enhancing neurogenesis.
Area of Science:
- Neuroscience
- Epigenetics
- Molecular Biology
Background:
- N6-methyladenosine (m6A) is a prevalent mRNA modification influencing various biological processes.
- The role of m6A in adult hippocampal neurogenesis and depression is not well understood.
Purpose of the Study:
- To elucidate the function and mechanism of m6A signaling in hippocampal neurogenesis and depression.
- To investigate the Mettl3-Ythdc2-Lrp2 axis in regulating neurogenesis.
Main Methods:
- Depletion and overexpression of Mettl3/Mettl14 in neural stem cells (NSCs).
- Assessment of m6A levels, cell proliferation, differentiation, and neurogenesis.
- Analysis of Lrp2 mRNA stability and translation efficiency.
- Behavioral tests in mice lacking Mettl3 and in a mouse model of depression.
Main Results:
- Mettl3/Mettl14 depletion reduced m6A, NSC proliferation, and neuronal genesis, while promoting glial differentiation.
- m6A modification of Lrp2 mRNA by Mettl3 enhanced its stability and translation via Ythdc2, promoting neurogenesis.
- Mice lacking Mettl3 exhibited impaired hippocampal neurogenesis, spatial memory deficits, and depression-like behaviors, which were reversed by Lrp2 overexpression or Mettl3 reintroduction.
Conclusions:
- m6A modification, particularly through the Mettl3-Ythdc2-Lrp2 pathway, plays a critical role in hippocampal neurogenesis.
- This pathway is implicated in depression-related behaviors.
- Targeting the Mettl3-Ythdc2-Lrp2 axis represents a potential therapeutic strategy for depression.
