CRMP-2 Is Involved in Axon Growth Inhibition Induced by RGMa In Vitro and In Vivo |
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Authors: | Tianzhu Wang Xiaohui Wu Cheng Yin Damon Klebe John H. Zhang Xinyue Qin |
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Affiliation: | 1. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China 2. Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, USA
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Abstract: | Repulsive guidance molecule-a (RGMa) is associated with axon growth inhibition in different central nervous system (CNS) injuries, but its signaling pathways remain unclear. We examined the involvement of collapsin response mediator protein-2 (CRMP-2), a common downstream target of Rho-kinase and GSK-3β, in vitro by culturing neonatal rat primary cortical neurons with RGMa protein, Rho-kinase inhibitor (Y-27632), and GSK-3β inhibitor. We examined CRMP-2 in vivo by suppressing RGMa expression using recombinant adenovirus (rAd-shRGMa) in a rat MCAO/reperfusion model. RGMa induced neurite retraction and CRMP-2 phosphorylation in vitro, which were reversed by either Rho-kinase or GSK-3β inhibitors. After MCAO/reperfusion in rats, pCRMP-2 protein was greatly increased in the ischemic cortex, axons were damaged severely, Neurofilament-200 (NF-200) expression was significantly decreased, and neurological deficits were significant, which were all improved by down-regulating RGMa. We concluded RGMa inhibits axon growth by phosphorylating CRMP-2 via both Rho-kinase and GSK-3β signaling pathways. |
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