Mettl3‐mediated m 6 A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant‐like effects
Abstract
N 6 ‐methyladenosine (m 6 A) is the most abundant mRNA modification affecting diverse biological processes. However, the functions and precise mechanisms of m 6 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 m 6 A abundance, proliferation, and neuronal genesis, coupled with enhanced glial differentiation. Conversely, overexpressing Mettl3 promoted proliferation and neuronal differentiation. Mechanistically, the m 6 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 m 6 A modification in Lrp2‐mediated neurogenesis via m 6 A‐binding protein Ythdc2, and propose a rationale that targeting Mettl3‐Ythdc2‐Lrp2 axis regulation of neurogenesis might serve as a promising antidepressant strategy.
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Targeting the METTL3-Ythdc2-LRP2 axis to regulate neurogenesis may be a promising antidepressant strategy.
“Targeting the METTL3-Ythdc2-LRP2 axis to regulate neurogenesis may be a promising antidepressant strategy.356”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [356]
METTL3 catalyzes the m6A modification of LRP2 mRNA to improve its stability and efficiency in translation, relying on reader protein Ythdc2, thereby facilitating neurogenesis.
“METTL3 catalyzes the m6A modification of the low-density lipoprotein receptor-related protein 2 (LRP2) mRNA to improve its stability and efficiency in translation. This process relies on reader protein YTH domain containing 2 (Ythdc2), thereby facilitating neurogenesis.356”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [356]
A deficit of METTL3 in mice lessens hippocampal neurogenesis, which induces spatial memory decline and depression-like behaviors.
“A deficit of METTL3 in mice lessens hippocampal neurogenesis, which induces spatial memory decline, and depression-like behaviors.”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [356]
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- Authors
- Xu, B., Li, Q., Wu, Y., Wang, H., Xu, J., Liu, H., & Xuan, A.
- Affiliations
- Second Affiliated Hospital of Guangzhou Medical University (CN)
- Corresponding author
- Xuan, Aiguo
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2022-06-18
- Volume
- 36
- Issue
- 7
- Pages
- e22392-e22392
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W4283073942
- Cited by
- 35
- References
- 43
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 2
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81371217)
- Natural Science Foundation of Guangdong Province (2022A1515012121)
- Guangzhou Medical University (JCXKJS2021C01, JCXKJS2021D08, JCXKJS2022A09)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- N6-methyladenosine, m6A RNA methylation, METTL3, METTL14, megalin, YTHDC2, mRNA stability, translation efficiency, adult hippocampal neurogenesis, neural stem cells, glial differentiation, depression, antidepressant-like effects, spatial memory
- MeSH terms
- Adenosine, Animals, Methyltransferases, RNA, Messenger, RNA Helicases, Low Density Lipoprotein Receptor-Related Protein-2, Mice, Neurogenesis
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