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.

中文翻译：

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MiR-615调控NSC的体外分化，并通过靶向LINGO-1促进脊髓损伤修复。

LINGO-1（LRR和含Ig域的NOGO受体相互作用蛋白1）是脊髓损伤（SCI）修复的可行靶标，因为它在神经元存活和轴突再生方面具有强大的负调控作用。尽管很有希望，但LINGO-1调控的细胞内机制尚不清楚。在这里，我们将miR-615鉴定为通过结合其3'-非翻译区（3'-UTR）直接靶向LINGO-1的潜在微RNA（miRNA），并引起LINGO-1的翻译抑制。MiR-615在神经干细胞（NSC）分化过程中对LINGO-1负调控，并促进其在体外的神经元分化。有趣的是，与对照相比，从miR-615治疗的NSC分化出的神经元具有短的过程，因此不成熟。进一步的结果表明，LINGO-1 /表皮生长因子受体（EGFR）信号可能参与该过程，因为使用特异性拮抗剂阻断EGFR会导致成熟的神经元具有较长的过程。此外，在SCI大鼠中鞘内施用miR-615阿戈密尔可有效降低LINGO-1，增加神经元存活率，增强轴突延伸和髓鞘形成以及改善后肢运动功能的恢复。因此，这项工作揭示了miR-615是调节NSC和SCI动物中LINGO-1的有效miRNA，并暗示miR-615是创伤性中枢神经系统（CNS）损伤的潜在治疗靶标。增加神经元存活，增强轴突延伸和髓鞘形成，并改善后肢运动功能的恢复。因此，这项工作揭示了miR-615是调控NSC和SCI动物中的LINGO-1的有效miRNA，并暗示miR-615作为创伤性中枢神经系统（CNS）损伤的潜在治疗靶标。增加神经元存活，增强轴突延伸和髓鞘形成，并改善后肢运动功能的恢复。因此，这项工作揭示了miR-615是调节NSC和SCI动物中LINGO-1的有效miRNA，并暗示miR-615是创伤性中枢神经系统（CNS）损伤的潜在治疗靶标。