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Lentiviral Delivery of miR-133b Improves Functional Recovery After Spinal Cord Injury in Mice

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Abstract

Based on the observation that microRNA (miRNA) 133b enhances regeneration after spinal cord injury in the adult zebrafish, we investigated whether this miRNA would be beneficial in a mammalian system in vitro and in vivo. We found that infection of cultured neurons with miR-133b promotes neurite outgrowth in vitro on an inhibitory substrate consisting of mixed chondroitin sulfate proteoglycans, when compared to infection with green fluorescent protein (GFP) for control. In vivo, viral infection of the injured adult mouse spinal cord at the time of injury at and in the vicinity of the lesion site enhanced expression of miR-133b. Measurements of locomotor recovery by Basso Mouse Scale (BMS) showed improvement of recovery starting at 4 weeks after injury and virus injection. This improvement was associated with downregulation of the expression levels of Ras homolog gene family member A (RhoA), chondroitin sulfate proteoglycans, and microglia/macrophage marker in the spinal cord as assayed 6 weeks after injury. Potential inhibitory molecules carrying consensus sequences for binding of miR-133b were identified in silico and verified in a reporter assay in vitro showing reductions in expression of RhoA, xylosyltransferase 1 (Xylt1), ephrin receptor A7 (Epha7), and purinergic receptor P2X ligand-gated ion channel 4 (P2RX4). These results encourage targeting miR-133 for therapy.

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Acknowledgments

We thank Ohyoon Kwon for contributing to the BMS scoring and Natasha Khatri for help with formatting. We are grateful to the New Jersey Commission on Spinal Cord Research for funding this project (CSCR12IRG014).

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    Authors and Affiliations

    1. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, 08554, USA

      Thomas Theis, Myung Yoo, Christopher S. Park, Jian Chen & Melitta Schachner

    2. Department of Neurology, Center Nanoscale Microscopy and Physiology of the Brain, University Medicine, Göttingen, Germany

      Sebastian Kügler

    3. Morehead State University, Morehead, KY, 40351, USA

      Kurt M. Gibbs

    4. Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

      Melitta Schachner

    5. Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou, Guangdong, 515041, China

      Melitta Schachner

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    Thomas Theis and Myung Yoo contributed equally to this work.

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    Fig. S1

    Transfection efficiencies of the pCMV constructs are not altered by different culture conditions. (a) Representative images of N2A cells co-transfected with pCMV-GFP-133b and empty pmirGlo plasmids (−), pmirGlo-Xylt1 (Xylt1), pmirGlo-Epha7 (Epha7), pmirGlo-P2RX4 (P2RX4), or pmirGlo-RhoA (RhoA) constructs. Scale bar, 10 μm. (b) The bar diagram shows the percentage of GFP-positive cells among all cells. (TIF 41,658 kb)

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    Theis, T., Yoo, M., Park, C.S. et al. Lentiviral Delivery of miR-133b Improves Functional Recovery After Spinal Cord Injury in Mice. Mol Neurobiol 54, 4659–4671 (2017). https://doi.org/10.1007/s12035-016-0007-z

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