The outgrowth of motor neurons needs to be enhanced for the efficient recovery of sensory and movement abilities after nerve injury. The microRNA miR-124-3p can repair spinal cord injury (SCI) and promote neurite outgrowth. In this study, we aimed to investigate the effect of miR-124-3p on neurite outgrowth and the mechanism underlying its effect on SCI. Rats with SCI were intrathecally injected with agomiR-124 (miR-124-3p agomiR) for 14 days. The agomiR-124 improved locomotor functions were observed with open-field scoring systems. The levels of miR-124-3p and Cortactin across three weeks, and neuronal biomarkers NF200, Tuj1, Map2 and NeuN post 6 weeks were reduced in rats with SCI, which were reverted with agomiR-124 treatment. The wound scratch assay showed that agomiR-124 enhanced outgrowth of neurites in PC12 cell-derived neuronal like cells. Silencing of Cttn reduced the numbers of neurites and growth cones, while pcDNA-Cttn exerted an opposite effect. The enhanced outgrowth of neurites by agomiR-124 can be reverted by co-treated si-Cttn. Finally, the interactions among miR-124-3p, IPO8, Ago1/2, and the Cttn promoter were verified in PC12 cells through RNA immunoprecipitation, RNA pull-down, and chromatin immunoprecipitation assays. Our results showed that miR-124-3p enhanced the function of neurons and promoted neurite outgrowth following SCI, at least partly by targeting the promoter of Cttn and activating its transcription. These findings elucidated the mechanism underlying the neuroprotective effects of miR-124-3p and revealed the therapeutic ability of the two molecules as targets associated with SCI.
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