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Molecular mechanism of METTL14-mediated m6A modification regulating microglial function post ischemic stroke
Xiaomin Zhang1, Pengyang Du1, Bo Bai1
1Department of Neurology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, China.
Brain Research Bulletin
|December 2, 2024
Summary
METTL14 promotes ischemic stroke by enhancing microglial M1 polarization. This involves m6A modification of PAX6 mRNA, leading to its degradation and increased TREM2 expression, worsening stroke outcomes.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Ischemic stroke triggers complex microglial responses.
- METTL14, an m6A methyltransferase, plays a role in cellular processes.
- Microglial polarization (M1/M2) is critical in stroke pathogenesis.
Purpose of the Study:
- To elucidate the molecular mechanism of METTL14 in regulating microglial function post-ischemic stroke.
- To investigate the role of the YTHDF2/PAX6/TREM2 axis in METTL14-mediated stroke pathology.
Main Methods:
- Established murine model of transient middle cerebral artery occlusion (tMCAO) and in vitro OGD/R model.
- Assessed neurological function (mNSS), infarct size (TTC), and microglial polarization (flow cytometry).
- Utilized qRT-PCR, Western blot, m6A quantification, RIP, ChIP, and dual-luciferase reporter assays.
Main Results:
- METTL14 expression was upregulated post-tMCAO; its inhibition improved neurological function and promoted M2 microglial polarization.
- METTL14 mediated m6A modification of PAX6 mRNA, promoting YTHDF2 binding and degradation.
- PAX6 directly bound to the TREM2 promoter, enhancing its transcription and expression.
Conclusions:
- METTL14 exacerbates ischemic stroke by promoting M1 microglial polarization.
- The YTHDF2/PAX6/TREM2 pathway is a key mediator of METTL14's detrimental effects in ischemic stroke.
