Nogo-A and Myelin-Associated Glycoprotein Mediate Neurite Growth Inhibition by Antagonistic Regulation of RhoA and Rac1

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 withY27632, 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.

[1]  Marco Domeniconi,et al.  Myelin-Associated Glycoprotein Interacts with the Nogo66 Receptor to Inhibit Neurite Outgrowth , 2002, Neuron.

[2]  A. Fournier,et al.  Myelin-Associated Glycoprotein as a Functional Ligand for the Nogo-66 Receptor , 2002, Science.

[3]  Zhigang He,et al.  Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth , 2002, Nature.

[4]  T. Yamashita,et al.  The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho , 2002, The Journal of cell biology.

[5]  K. Aktories,et al.  Rac1 and Cdc42 but Not RhoA or Rho Kinase Activities Are Required for Neurite Outgrowth Induced by the Netrin-1 Receptor DCC (Deleted in Colorectal Cancer) in N1E-115 Neuroblastoma Cells* , 2002, The Journal of Biological Chemistry.

[6]  T. Uemura,et al.  Control of Actin Reorganization by Slingshot, a Family of Phosphatases that Dephosphorylate ADF/Cofilin , 2002, Cell.

[7]  S. Strittmatter,et al.  Semaphorin-mediated axonal guidance via Rho-related G proteins. , 2001, Current opinion in cell biology.

[8]  M. Filbin,et al.  Soluble Myelin-Associated Glycoprotein Released from Damaged White Matter Inhibits Axonal Regeneration , 2001, Molecular and Cellular Neuroscience.

[9]  L. Facci,et al.  Myelin-associated Glycoprotein Interacts with Ganglioside GT1b , 2001, Journal of Biological Chemistry.

[10]  M. Greenberg,et al.  EphA Receptors Regulate Growth Cone Dynamics through the Novel Guanine Nucleotide Exchange Factor Ephexin , 2001, Cell.

[11]  Y. Goshima,et al.  Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse , 2001, Nature Neuroscience.

[12]  Hailan Hu,et al.  Plexin-B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho , 2001, Current Biology.

[13]  B. Dickson Rho GTPases in growth cone guidance , 2001, Current Opinion in Neurobiology.

[14]  A. Fournier,et al.  Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration , 2001, Nature.

[15]  L. Luo RHO GTPASES in neuronal morphogenesis , 2000, Nature Reviews Neuroscience.

[16]  M. Kirschner,et al.  Mechanism of N-Wasp Activation by Cdc42 and Phosphatidylinositol 4,5-Bisphosphate , 2000, The Journal of cell biology.

[17]  A. Hall,et al.  Rho GTPases and their effector proteins. , 2000, The Biochemical journal.

[18]  S. Narumiya,et al.  A Critical Role for a Rho-Associated Kinase, p160ROCK, in Determining Axon Outgrowth in Mammalian CNS Neurons , 2000, Neuron.

[19]  S. Narumiya,et al.  Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. , 2000, Molecular pharmacology.

[20]  T. Takenawa,et al.  Essential Role of Neural Wiskott-Aldrich Syndrome Protein in Neurite Extension in PC12 Cells and Rat Hippocampal Primary Culture Cells* , 2000, The Journal of Biological Chemistry.

[21]  K. Aktories,et al.  Ephrin-A5 Induces Collapse of Growth Cones by Activating Rho and Rho Kinase , 2000, The Journal of cell biology.

[22]  Fumio Nakamura,et al.  Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein , 2000, Nature.

[23]  R. Prinjha,et al.  Neurobiology: Inhibitor of neurite outgrowth in humans , 2000, Nature.

[24]  Martin E. Schwab,et al.  Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1 , 2000, Nature.

[25]  M. Schwab,et al.  Nogo-A, a Potent Inhibitor of Neurite Outgrowth and Regeneration , 2000, Biological chemistry.

[26]  M. Filbin,et al.  Glial inhibition of nerve regeneration in the mature mammalian CNS , 2000, Glia.

[27]  M. Schwab,et al.  Bovine CNS Myelin Contains Neurite Growth-Inhibitory Activity Associated with Chondroitin Sulfate Proteoglycans , 1999, The Journal of Neuroscience.

[28]  C. Bandtlow,et al.  Differential Cytoskeletal Changes during Growth Cone Collapse in Response to hSema III and Thrombin , 1999, Molecular and Cellular Neuroscience.

[29]  B. Eickholt,et al.  Sema3A-induced growth-cone collapse is mediated by Rac1 amino acids 17–32 , 1999, Current Biology.

[30]  N. Leclerc,et al.  Inactivation of Rho Signaling Pathway Promotes CNS Axon Regeneration , 1999, The Journal of Neuroscience.

[31]  S. Narumiya,et al.  Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. , 1999, Science.

[32]  J. Hartwig,et al.  Lipid kinases are novel effectors of the GTPase Rac1. , 1999, Advances in enzyme regulation.

[33]  A. Turnley,et al.  Nerve growth factor modulates myelin-associatedglycoprotein binding to sensory neurons , 1999, International Journal of Developmental Neuroscience.

[34]  G. Bokoch,et al.  Inhibition of myosin light chain kinase by p21-activated kinase. , 1999, Science.

[35]  W. Kiosses,et al.  Regulation of the small GTP‐binding protein Rho by cell adhesion and the cytoskeleton , 1999, The EMBO journal.

[36]  G. Prestwich,et al.  Type I Phosphatidylinositol-4-phosphate 5-Kinases Synthesize the Novel Lipids Phosphatidylinositol 3,5-Bisphosphate and Phosphatidylinositol 5-Phosphate* , 1998, The Journal of Biological Chemistry.

[37]  S. Narumiya,et al.  Molecular Dissection of the Rho-associated Protein Kinase (p160ROCK)-regulated Neurite Remodeling in Neuroblastoma N1E-115 Cells , 1998, The Journal of cell biology.

[38]  P. Caroni,et al.  Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase , 1998, Nature.

[39]  E. Nishida,et al.  Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization , 1998, Nature.

[40]  M. Filbin,et al.  Soluble Myelin-Associated Glycoprotein (MAG) Foundin VivoInhibits Axonal Regeneration , 1997, Molecular and Cellular Neuroscience.

[41]  S. Strittmatter,et al.  Rac1 Mediates Collapsin-1-Induced Growth Cone Collapse , 1997, The Journal of Neuroscience.

[42]  Marie-France Carlier,et al.  Actin Depolymerizing Factor (ADF/Cofilin) Enhances the Rate of Filament Turnover: Implication in Actin-based Motility , 1997, The Journal of cell biology.

[43]  S. B. Kater,et al.  Myelin‐associated glycoprotein inhibits neurite/axon growth and causes growth cone collapse , 1996, Journal of neuroscience research.

[44]  Yoshiharu Matsuura,et al.  Phosphorylation and Activation of Myosin by Rho-associated Kinase (Rho-kinase)* , 1996, The Journal of Biological Chemistry.

[45]  Kozo Kaibuchi,et al.  Regulation of Myosin Phosphatase by Rho and Rho-Associated Kinase (Rho-Kinase) , 1996, Science.

[46]  M. Schachner,et al.  Disruption of the Gene for the Myelin-Associated Glycoprotein Improves Axonal Regrowth along Myelin in C57BL/Wlds Mice , 1996, Neuron.

[47]  M. Filbin,et al.  Myelin-Associated Glycoprotein Inhibits Axonal Regeneration from a Variety of Neurons via Interaction with a Sialoglycoprotein , 1996, Molecular and Cellular Neuroscience.

[48]  B. Dérijard,et al.  Cdc42 and PAK-mediated Signaling Leads to Jun Kinase and p38 Mitogen-activated Protein Kinase Activation (*) , 1995, The Journal of Biological Chemistry.

[49]  D. Drubin,et al.  The ADF/cofilin proteins: stimulus-responsive modulators of actin dynamics. , 1995, Molecular biology of the cell.

[50]  C. Hall,et al.  Molecular Cloning of a New Member of the p21-Cdc42/Rac-activated Kinase (PAK) Family (*) , 1995, The Journal of Biological Chemistry.

[51]  L. Cantley,et al.  Rho Family GTPases Bind to Phosphoinositide Kinases (*) , 1995, The Journal of Biological Chemistry.

[52]  M. Filbin,et al.  A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration , 1994, Neuron.

[53]  C. Bandtlow,et al.  Oligodendrocytes arrest neurite growth by contact inhibition , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[54]  P. Leder,et al.  The kit ligand: A cell surface molecule altered in steel mutant fibroblasts , 1990, Cell.

[55]  J. John,et al.  ras p21 protein promotes survival and fiber outgrowth of cultured embryonic neurons , 1989, Neuron.

[56]  M. Hatten,et al.  Neuronal regulation of astroglial morphology and proliferation in vitro , 1985, The Journal of cell biology.

[57]  M. Eisenstein,et al.  Oligomerization reduces heparin affinity but enhances receptor binding of fibroblast growth factor 2. , 2000, The Biochemical journal.

[58]  S. Narumiya,et al.  A Critical Role for a Rho-Associated Kinase p160ROCK in Determining Axon Outgrowth in Mammalian CNS Neurons , 2000 .

[59]  J. Bamburg,et al.  Actin depolymerizing factor and cofilin phosphorylation dynamics: response to signals that regulate neurite extension. , 1998, Cell motility and the cytoskeleton.

[60]  M. Chao,et al.  Mesenchymal and neuronal cell expression of the p75 neurotrophin receptor gene occur by different mechanisms. , 1995, Developmental biology.

[61]  P. Janmey,et al.  Modulation of gelsolin function by phosphatidylinositol 4,5-bisphosphate , 1987, Nature.