Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Antibodies / immunology
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Antibodies / isolation & purification
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Antibodies / pharmacology
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CHO Cells
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cells, Cultured
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Coculture Techniques
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Cricetinae
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GPI-Linked Proteins
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Growth Cones / metabolism*
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Growth Cones / ultrastructure
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Growth Inhibitors / antagonists & inhibitors
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Growth Inhibitors / metabolism*
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Immunoglobulin G / pharmacology
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Injections, Spinal
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / metabolism*
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Nerve Regeneration / drug effects
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Nerve Regeneration / physiology*
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / metabolism*
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Pyramidal Tracts / cytology
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Pyramidal Tracts / drug effects
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Pyramidal Tracts / metabolism
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Rats
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Recovery of Function / drug effects
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Recovery of Function / physiology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Spinal Cord / cytology
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Spinal Cord / drug effects
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Spinal Cord / metabolism*
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Spinal Cord Injuries / metabolism*
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Spinal Cord Injuries / physiopathology
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Up-Regulation / physiology
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rhoA GTP-Binding Protein / metabolism
Substances
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Antibodies
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GPI-Linked Proteins
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Growth Inhibitors
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Immunoglobulin G
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Membrane Glycoproteins
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Nerve Tissue Proteins
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RGM protein, rat
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rhoA GTP-Binding Protein