Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (6): 2476-2486.doi: 10.4103/NRR.NRR-D-24-00081

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MicroRNA-301a knockout attenuates peripheral nerve regeneration by delaying Wallerian degeneration

Lanya Fu1, 2, Xiaofang Hu1, 2, Jiawei Xu1, 2, Zhenlin Li1, 2, Jiale Cai1, 2, Xinrui Ma1, 2, Ying Zou1, 2, Ye He1, 2, Shuyi Xu1, 2, Yizhou Xu1, 2, 3, Jiaqi Zhang1, 2, Yunlun Li1, 2, Jingmin Liu1, 2, Tsz Hei Fong1, 2, Xianghai Wang1, 2, Lixin Zhu3 , Dongfeng Chen4 , Aijun Liu4 , Xiaodong Ma5 , Jiasong Guo1, 2, 3, *   

  1. 1 Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration Center for Experimental Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China;  2 Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, Guangdong Province, China;  3 Department of Spine Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China;  4 Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China;  5 Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, Guangdong Province, China
  • Online:2026-06-15 Published:2025-09-19
  • Contact: Jiasong Guo, PhD, jiasongguo@smu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 82071386 (to JG).

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Abstract: Our recent study demonstrated that knockout of microRNA-301a attenuates migration and phagocytosis in macrophages. Considering that macrophages and Schwann cells synergistically clear the debris of degraded axons and myelin during Wallerian degeneration, which is a prerequisite for nerve regeneration, we hypothesized that microRNA-301a regulates Wallerian degeneration and nerve regeneration via impacts on Schwann cell migration and phagocytosis. Herein, we found low expression of microRNA-301a in intact sciatic nerves, with no impact of the microRNA-301a knockout on nerve structure and function. By contrast, we found significant upregulation of microRNA-301a in injured sciatic nerves. We established a sciatic nerve crush model in microRNA-301a knockout mice, which exhibited attenuated morphological and functional regeneration following sciatic nerve crush injury. The microRNA-301a knockout also led to significantly inhibited Wallerian degeneration in an in vivo sciatic nerve-transection model and in an in vitro nerve explant block model. Schwann cells with the microRNA-301a knockout showed inhibition of phagocytosis and migration, which was reversible under transfection with microRNA-301a mimics. Rescue experiments involving transfection of microRNA-301a-knockout Schwann cells with microRNA-301a mimics or treatment with the C–X–C motif receptor 4 inhibitor WZ811 indicated the mechanistic involvement of the Yin Yang 1/C–X–C motif receptor 4 pathway in the role of microRNA-301a. Combined with our previous findings in macrophages, we conclude that microRNA-301a plays a key role in peripheral nerve injury and repair by regulating the migratory and phagocytic capabilities of Schwann cells and macrophages via the Yin Yang 1/C–X–C motif receptor 4 pathway.

Key words: axonal regeneration, CXCR4, macrophage, migration, miR-301a, peripheral nerve injury, phagocytosis, remyelination, Schwann cell, Wallerian degeneration, YY1