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Knockout of METTL3 promotes neural functional recovery after spinal cord injury in mice via the USP4/YTHDF2 axis

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Abstract

Background

Spinal cord injury (SCI) can cause destructive neurological dysfunctions.

Objectives

The present study investigates the role and mechanism of methyltransferase like 3 (METTL3) in neural functional recovery post-SCI.

Results

SCI mice showed neurological function impairment, with significantly elevated METTL3 expression and m6A content. METTL3 inhibition improved motor and sensory injury in SCI mice, alleviated tissue injury, up-regulated BDNF, GDNF, and IL-10 levels, and down-regulated IL-1β and TNF-α levels. Mechanistically, METTL3 mediated m6A modification of USP4 mRNA and enhanced YTHDF2 enrichment on USP4 mRNA, thus reducing USP4 mRNA stability and expression. Combined experiments confirmed that METTL3 exacerbated neurological impairment in SCI mice by reducing USP4 expression.

Conclusion

METTL3-dominated m6A modification enhances YTHDF2 enrichment on USP4 mRNA and thereby reduces USP4 mRNA stability, eventually aggravating neurological impairment in SCI mice.

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Data availability

The data used to support the findings of this study are available from the corresponding authors upon request.

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Acknowledgments

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Funding

There was no funding for the study.

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Authors and Affiliations

  1. Department of Pain, The First Affiliated Hospital of Nanchang University, No. 17, Yongwai Zheng Street, Nanchang, 330000, Jiangxi, China

    Yanbo Yu, Zhisheng Wu, Ziqiang Yu & Daying Zhang

Authors
  1. Yanbo Yu
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  2. Zhisheng Wu
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  3. Ziqiang Yu
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  4. Daying Zhang
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Contributions

YY conducted the experiment and wrote the manuscript. YY and ZW designed the structure of the article. ZY and DZ were responsible for the literature searches and analyses. All authors contributed to and have approved the final article.

Corresponding author

Correspondence to Daying Zhang.

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Conflict of interest

Yanbo Yu, Zhisheng Wu, Ziqiang Yu and Daying Zhang declare no conflicts of interest.

Ethical approval

All animal experiment schemes were approved by the Animal Ethics Committee of The First Affiliated Hospital of Nanchang University. Animal experiments were implemented based on the Guide for the Care and Use of Laboratory Animals (National Research Council (US) 2011).

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Yu, Y., Wu, Z., Yu, Z. et al. Knockout of METTL3 promotes neural functional recovery after spinal cord injury in mice via the USP4/YTHDF2 axis. Mol. Cell. Toxicol. (2023). https://doi.org/10.1007/s13273-023-00393-8

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