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

Fu Lanya,Hu Xiaofang,Xu Jiawei,Li Zhenlin,Cai Jiale,Ma Xinrui,Zou Ying,He Ye,Xu Shuyi,Xu Yizhou,Zhang Jiaqi,Li Yunlun,Liu Jingmin,Fong Tsz Hei,Wang Xianghai,Zhu Lixin,Chen Dongfeng,Liu Aijun,Ma Xiaodong,Guo Jiasong

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.