Abstract
The adult mammalian CNS has a limited capacity for nerve regeneration and structural plasticity. The presence of glia-derived inhibitory factors myelin-associated glycoprotein (MAG) and Nogo-A have been suggested to provide a nonpermissive environment for elongating nerve fibers. In particular, Nogo-A, an integral membrane protein predominantly expressed by oligodendrocytes, has been demonstrated to impair neurite growth in vitro and in vivo. Structure function analysis revealed that Nogo-A protein contains at least two active domains, NiG and Nogo-66, with diverse effects on neurite outgrowth and cell spreading. We now provide evidence that these inhibitory domains mediate their effects via an antagonistic regulation of the small GTPases RhoA and Rac1, resulting in activation of RhoA and suppression of Rac1. By inactivating RhoA with C3 transferase or the downstream effector Rho-kinase ROCK with, the inhibitory effects of both Nogo-A fragments and MAG on neurite outgrowth and oligodendrocyte-mediated growth cone collapse were abolished. Furthermore, we show that the recently cloned receptor for Nogo-66 and MAG, NgR, is not necessary for either NiG- or MAG-induced RhoA activation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / pharmacology
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Animals
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CHO Cells
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Cell Communication / drug effects
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Cell Communication / physiology
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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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Enzyme Inhibitors / pharmacology
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GPI-Linked Proteins
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Gene Expression Regulation / physiology
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Growth Cones / drug effects
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Growth Cones / physiology
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Humans
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Intracellular Signaling Peptides and Proteins
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Kidney / cytology
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Kidney / metabolism
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Microscopy, Video
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Myelin Proteins / chemistry
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Myelin Proteins / genetics
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Myelin Proteins / metabolism*
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Myelin Proteins / pharmacology
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Myelin-Associated Glycoprotein / metabolism*
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Myelin-Associated Glycoprotein / pharmacology
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Neurites / drug effects
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Neurites / metabolism*
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism
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Nogo Proteins
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Nogo Receptor 1
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Oligodendroglia / cytology
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Peptide Fragments / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Structure, Tertiary / physiology
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Pyridines / pharmacology
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Rats
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Receptors, Cell Surface / metabolism
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rac1 GTP-Binding Protein / metabolism*
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rho-Associated Kinases
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rhoA GTP-Binding Protein / antagonists & inhibitors
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rhoA GTP-Binding Protein / metabolism*
Substances
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Amides
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Enzyme Inhibitors
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GPI-Linked Proteins
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Intracellular Signaling Peptides and Proteins
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Myelin Proteins
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Myelin-Associated Glycoprotein
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Nogo Proteins
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Nogo Receptor 1
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Peptide Fragments
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Pyridines
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RTN4 protein, human
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RTN4R protein, human
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Receptors, Cell Surface
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Rtn4 protein, rat
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Rtn4r protein, rat
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Y 27632
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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rac1 GTP-Binding Protein
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rhoA GTP-Binding Protein