The inhibitory activity associated with myelin is a major obstacle for successful axon regeneration in the adult mammalian central nervous system (CNS)1,2. In addition to myelin-associated glycoprotein (MAG)3,4 and Nogo-A5,6,7, available evidence suggests the existence of additional inhibitors in CNS myelin8. We show here that a glycosylphosphatidylinositol (GPI)-anchored CNS myelin protein, oligodendrocyte-myelin glycoprotein (OMgp), is a potent inhibitor of neurite outgrowth in cultured neurons. Like Nogo-A, OMgp contributes significantly to the inhibitory activity associated with CNS myelin. To further elucidate the mechanisms that mediate this inhibitory activity of OMgp, we screened an expression library and identified the Nogo receptor (NgR)9 as a high-affinity OMgp-binding protein. Cleavage of NgR and other GPI-linked proteins from the cell surface renders axons of dorsal root ganglia insensitive to OMgp. Introduction of exogenous NgR confers OMgp responsiveness to otherwise insensitive neurons. Thus, OMgp is an important inhibitor of neurite outgrowth that acts through NgR and its associated receptor complex. Interfering with the OMgp/NgR pathway may allow lesioned axons to regenerate after injury in vivo.
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Schwab, M. E. & Bartholdi, D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol. Rev. 76, 319–370 (1996)
Horner, P. J. & Gage, F. H. Regenerating the damaged central nervous system. Nature 407, 963–970 (2000)
McKerracher, L. et al. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805–811 (1994)
Mukhopadhyay, G. et al. A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron 13, 757–767 (1994)
Chen, M. S. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434–439 (2000)
GrandPre, T., Nakamura, F., Vartanian, T. & Strittmatter, S. M. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403, 439–444 (2000)
Prinjha, R. et al. Inhibitor of neurite outgrowth in humans. Nature 403, 383–384 (2000)
Tessier-Lavigne, M. & Goodman, C. S. Perspectives: neurobiology. Regeneration in the Nogo zone. Science 287, 813–814 (2000)
Fournier, A. E., GrandPre, T. & Strittmatter, S. M. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341–346 (2001)
Luo, Y., Raible, D. & Raper, J. A. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75, 217–227 (1993)
Mikol, D. D. & Stefansson, K. A phosphatidylinositol-linked peanut agglutinin-binding glycoprotein in central nervous system myelin and on oligodendrocytes. J. Cell Biol. 106, 1273–1279 (1988)
Mikol, D. D., Gulcher, J. R. & Stefansson, K. The oligodendrocyte-myelin glycoprotein belongs to a distinct family of proteins and contains the HNK-1 carbohydrate. J. Cell Biol. 110, 471–479 (1990)
He, Z. & Tessier-Lavigne, M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 90, 739–751 (1997)
Habib, A. A. et al. Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system. J. Neurochem. 70, 1704–1711 (1998)
Niederost, B. P., Zimmermann, D. R., Schwab, M. E. & Bandtlow, C. E. Bovine CNS myelin contains neurite growth-inhibitory activity associated with chondroitin sulfate proteoglycans. J. Neurosci. 19, 8979–8989 (1999)
Spillmann, A. A., Bandtlow, C. E., Lottspeich, F., Keller, F. & Schwab, M. E. Identification and characterization of a bovine neurite growth inhibitor (bNI-220). J. Biol Chem. 273, 19283–19293 (1998)
Flanagan, J. G. & Cheng, H. J. Alkaline phosphatase fusion proteins for molecular characterization and cloning of receptors and their ligands. Methods Enzymol. 327, 198–210 (2000)
Liu, B. P. & Strittmatter, S. M. Semaphorin-mediated axonal guidance via Rho-related G proteins. Curr. Opin. Cell. Biol. 13, 619–626 (2001)
Norton, W. T. & Poduslo, S. E. Myelination in rat brain: method of myelin isolation. J. Neurochem. 21, 749–757 (1973)
Neve, R. L., Howe, J. R., Hong, S. & Kalb, R. G. Introduction of the glutamate receptor subunit 1 into motor neurons in vitro and in vivo using recombinant herpes simplex virus. Neuroscience 79, 435–447 (1997)
Huang, D. W., McKerracher, L., Braun, P. E. & David, S. A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord. Neuron 24, 639–647 (1999)
Takahashi, T., Nakamura, F., Jin, Z., Kalb, R. G. & Strittmatter, S. M. Semaphorins A and E act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors. Nature Neurosci. 1, 487–493 (1998)
Cohen-Cory, S. & Fraser, S. E. Effects of brain-derived neurotrophic factor on optic axon branching and remodeling in vivo. Nature 378, 192–196 (1995)
We thank A. Habib and J. Flanagan for providing the anti-OMgp antibodies and the AP-5 plasmid, and M. Greenberg, X. He, D. Lowenstein and M. Tessier-Lavigne for reading the manuscript. This study was supported by the Alfred Sloan Foundation, the Burroughs Wellcome Fund, the EJLB Foundation, the International Spinal Research Trust, the John Merck Fund, the Klingenstein Fund, the Whitehall Foundation, and the National Institutes of Health (NIH). K.C.W. is a recipient of a Howard Hughes Predoctoral Fellowship. V.K. is supported by an NIH predoctoral training grant.
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