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Published online 3 April 2006. doi:10.1083/jcb.200508143
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 1, 47-58
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Article

RGMa inhibition promotes axonal growth and recovery after spinal cord injury



Katsuhiko Hata1, Masashi Fujitani1, Yuichi Yasuda2, Hideo Doya1, Tomoko Saito1, Satoru Yamagishi1, Bernhard K. Mueller3, and Toshihide Yamashita1

1 Department of Neurobiology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan
2 Central Research Laboratories, Sysmex Corporation, Nishi-ku, Kobe 651-22, Japan
3 Central Nervous System Research, Abbott GmbH and Company KG, 67061 Ludwigshafen, Germany

Correspondence to Toshihide Yamashita: t-yamashita{at}faculty.chiba-u.jp

Repulsive guidance molecule (RGM) is a protein implicated in both axonal guidance and neural tube closure. We report RGMa as a potent inhibitor of axon regeneration in the adult central nervous system (CNS). RGMa inhibits mammalian CNS neurite outgrowth by a mechanism dependent on the activation of the RhoA–Rho kinase pathway. RGMa expression is observed in oligodendrocytes, myelinated fibers, and neurons of the adult rat spinal cord and is induced around the injury site after spinal cord injury. We developed an antibody to RGMa that efficiently blocks the effect of RGMa in vitro. Intrathecal administration of the antibody to rats with thoracic spinal cord hemisection results in significant axonal growth of the corticospinal tract and improves functional recovery. Thus, RGMa plays an important role in limiting axonal regeneration after CNS injury and the RGMa antibody offers a possible therapeutic agent in clinical conditions characterized by a failure of CNS regeneration.

Abbreviations used in this article: BBB, Basso-Beattie-Bresnahan locomotor rating scale; BDA, biotin-dextran amine; CNS, central nervous system; CSPG, chondroitin sulfate proteoglycan; CST, corticospinal tract; GFAP, glial fibrillary acidic protein; IB4, isolectin B4; MAG, myelin-associated glycoprotein; MOSP, myelin/oligodendrocyte-specific protein; NgR, Nogo receptor; OMgp, oligodendrocyte-myelin glycoprotein; PI-PLC, phosphatidylinositol-specific PLC; PLL, poly-L-lysine; RGM, repulsive guidance molecule; SCI, spinal cord injury; Tuj1, neuron-specific ß tubulin III protein.


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