Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (6): 1749-1763.doi: 10.4103/NRR.NRR-D-23-01477

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Enhancing m6 A modification in the motor cortex facilitates corticospinal tract remodeling after spinal cord injury

Tian Qin1, 2, 3, #, Yuxin Jin1, 2, 3, #, Yiming Qin1, 2, 3, Feifei Yuan1, 2, 3, Hongbin Lu2, 3, 4, Jianzhong Hu1, 2, 3, *, Yong Cao1, 2, 3, *, Chengjun Li2, 3, 4, *   

  1. 1 Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan Province, China;   2 Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, Hunan Province, China;  3 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, China;   4 Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
  • Online:2025-06-15 Published:2024-11-12
  • About author:Jianzhong Hu, PhD, jianzhonghu@csu.edu.cn or jianzhonghu@hotmail.com;Yong Cao, PhD, xycaoyong@csu.edu.cn or caoyong1912@163.com; Chengjun Li, PhD, 443555063@qq.com or lichengjun1992@hotmail.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82030071 (to JH), 82272495 (to YC); Science and Technology Major Project of Changsha, No. kh2103008 (to JH); and Graduate Students’ Independent Innovative Projects of Hunan Province, No. CX20230311 (to YJ).

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Abstract: Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6 -methyladenosine (m6 A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m6 A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein (METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m6 A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m6 A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m6 A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.

Key words: corticospinal tract remodeling, epigenetic regulations, locomotor cortex, m6 A modification, methyltransferase 14 protein (METTL14), mitogen-activated protein kinase, neural regeneration, spinal cord injury, syringin, TRIB2