MiR-615 Regulates NSC Differentiation In Vitro and Contributes to Spinal Cord Injury Repair by Targeting LINGO-1.

LINGO-1(LRR and Ig domain-containing NOGO receptor interacting protein 1) is a viable target for spinal cord injury (SCI) repair due to its potent negative regulation in neuron survival and axonal regeneration. Although promising, the intracellular mechanism underlying LINGO-1 regulation is unclear. Here, we identified miR-615 as a potential microRNA (miRNA) that directly targets LINGO-1 by binding its 3'-untranslated region (3'-UTR) and caused the translation inhibition of LINGO-1. MiR-615 negatively regulated LINGO-1 during neural stem cell (NSC) differentiation and facilitated its neuronal differentiation in vitro. Interestingly, compared to the control, neurons differentiated from miR-615-treated NSCs were immature with short processes. Further results showed LINGO-1/epidermal growth factor receptor (EGFR) signaling may be involved in this process, as blockade of EGFR using specific antagonist resulted in mature neurons with long processes. Furthermore, intrathecal administration of miR-615 agomir in SCI rats effectively knocked down LINGO-1, increased neuronal survival, enhanced axonal extension and myelination, and improved recovery of hindlimbs motor functions. This work thus uncovers miR-615 as an effective miRNA that regulates LINGO-1 in NSC and SCI animals, and suggests miR-615 as a potential therapeutic target for traumatic central nervous system (CNS) injury.