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

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Abstract

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.

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Funding

This work was financially supported by the National Natural Science Foundation of China, No. 81371366 (to HFW); the Characteristic Innovation Project of Colleges and Universities in Guangdong Province, No. 2018KTSCX075 (to HFW); the Key Project of Social Development of Dongguan of China, No. 20185071521640 (to HFW); College Students’ Science and Technology Innovation Training Project, No. 201810571058, No. GDMU2018024, No. GDMU2018056, No. GDMU2018061 (to HFW); College Students’ Innovative Experimental Project in Guangdong Medical University, No. ZZDS001 (to HFW); and College Students’ Science and Technology Innovation Cultivation Project in Guangdong, No. pdjh2019b0217 (to HFW).

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  1. Hongfu Wu, Lu Ding and Yuhui Wang contributed equally to this work.

Authors and Affiliations

  1. Institute of Stem Cells and Regenerative Medicine, Department of Physiology, Guangdong Medical University, No. 1, Xin Cheng Road, Songshan Lake, Dongguan, 523808, China

    Hongfu Wu, Lu Ding, Xiaomin Zhang & Kangzhen Chen

  2. Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China

    Lu Ding

  3. Department of Surgery, The Third Hospital of Guangdong Medical University (Longjiang Hospital of Shunde District), Foshan, Guangdong, China

    Yuhui Wang, Tao Wang, Yong Lin & Caitang Zhong

  4. Department of Nutrition and Food Hygiene, Guangdong Medical University, Dongguan, China

    Tang-Bin Zou

  5. Clinical Laboratory, Dongguan Municipal Houjie Hospital of Guangdong Medical University, Dongguan, Guangdong, China

    Wenjin Fu

  6. Hand & Foot Surgery, Dongguan Municipal Houjie Hospital of Guangdong Medical University, Dongguan, Guangdong, China

    Yutian Lei

  7. Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, No.628, Zhenyuan Road, Xinhu Street, Guangming New District, Shenzhen, 518107, China

    Chuanming Luo

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  1. Hongfu Wu
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Wu, H., Ding, L., Wang, Y. et al. MiR-615 Regulates NSC Differentiation In Vitro and Contributes to Spinal Cord Injury Repair by Targeting LINGO-1. Mol Neurobiol 57, 3057–3074 (2020). https://doi.org/10.1007/s12035-020-01936-z

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