Journal of Neurocytology

, Volume 31, Issue 2, pp 93–120 | Cite as

The Nogo receptor, its ligands and axonal regeneration in the spinal cord; A review

  • D. Hunt
  • R.S. Coffin
  • P.N. Anderson


At least three proteins present in CNS myelin, Nogo, MAG and OMgp are capable of causing growth cone collapse and inhibiting neurite outgrowth in vitro. Surprisingly, Nogo and OMgp are also strongly expressed by many neurons (including neocortical projection cells). Nogo expression is increased by some cells at the borders of CNS lesion sites and by cells in injured peripheral nerves, but Nogo and CNS myelin are largely absent from spinal cord injury sites, which are none the less strongly inhibitory to axonal regeneration. Nogo is found on growing axons during development, suggesting possible functions for neuronal Nogo in axon guidance. Although Nogo, MAG and OMgp lack sequence homologies, they all bind to the Nogo receptor (NgR), a GPI-linked cell surface molecule which, in turn, binds p75 to activate RhoA. NgR is strongly expressed by cerebral cortical neurons but many other neurons express NgR weakly or not at all. Some neurons, such as DRG cells, respond to Nogo and CNS myelin in vitro although they express little or no NgR in vivo which, with other data, indicates that other receptors are available for NgR ligands. NgR expression is unaffected by injury to the nervous system, and there is no clear correlation between NgR expression by neurons and lack of regenerative ability. In the injured spinal cord, interactions between NgR and its ligands are most likely to be important for limiting regeneration of corticospinal and some other descending tracts; other receptors may be more important for ascending tracts. Antibodies to Nogo, mainly the poorly-characterised IN-1 or its derivatives, have been shown to enhance recovery from partial transections of the spinal cord. They induce considerable plasticity from the axons of corticospinal neurons, including sprouting across the midline and, to a limited extent, regeneration around the lesion. Regeneration of corticospinal axons induced by Nogo antibodies has not yet been demonstrated after complete transections or contusion injuries of the spinal cord. It is not clear whether antibodies against Nogo act on oligodendrocytes/myelin or by binding to neuronal Nogo, or whether they can stimulate regeneration of ascending axons in the spinal cord, most of which express little or no NgR. Despite these uncertainties, however, NgR and its ligands offer important new targets for enhancing plasticity and regeneration in the nervous system.


Spinal Cord Spinal Cord Injury Nogo Axonal Regeneration Injured Spinal Cord 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aizawa, H., Wakatsuki, S., Ishii, A., Moriyama, K., Sasaki, Y., Ohashi, K., Sekine-Aizawa, Y., Sehara-Fujisawa, A., Mizuno, K., Goshima, Y. & Yahara, I. (2001) Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse. Nature Neuroscience 4, 367–373.PubMedGoogle Scholar
  2. Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. (1990) Basic local alignment search tool. Journal of Molecular Biology 215, 403–410.PubMedGoogle Scholar
  3. Altschul, S. F., Madden, T. L., Schaffer, A. A., Zhang, J., Zhang, Z., Miller, W. & Lipman, D. J. (1997) Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Research 25, 3389–3402.PubMedGoogle Scholar
  4. Anderson, P. N. & Lieberman, A. R. (1999) Intrinsic determinants of differential axonal regeneration by adult mammalian CNS neurons. In Degeneration and Regeneration in the Nervous System (edited by Saunders N. R. & Dziegielewska K. M.) pp. 53–75. Harwood Academic Press.Google Scholar
  5. Anderson, P. N., Campbell, G., Zhang, Y. & Lieberman, A. R. (1998) Cellular and molecular correlates of the regeneration of adult mammalian CNS axons into peripheral nerve grafts. Progress in Brain Research 117, 211–232.PubMedGoogle Scholar
  6. Anderson, P. N., Rezajooi, K., Pavlides, M, Stallcup, W. B., Winterbottom, J., Tohyama, K. & Lieberman, A. R. Ng2 expression increases following injury to the spinal cord or peripheral nerves. Program No. 529.12 2002 Abstracts viewer/Itinerary planner. Washington, DC: Society for Neuroscience, 2002. CD-ROM.Google Scholar
  7. Bandtlow, C. E., Schmidt, M. F., Hassinger, T. D., Schwab, M. E. & Kater, S. B. (1993) Role of in tracellular calcium in NI-35-evoked collapse of neuronal growth cones. Science 259, 80–83.PubMedGoogle Scholar
  8. Bandtlow, C. E. & Schwab, M. E. (2000) NI-35/250/nogo-a: A neurite growth inhibitor restricting structural plasticity and regeneration of nerve fibers in the adult vertebrate CNS. Glia 29, 175–181.PubMedGoogle Scholar
  9. Bareyre, F. M., Haudenschild, B. & Schwab, M. E. (2002) Long-lasting sprouting and gene expression changes induced by the monoclonal antibody IN-1 in the adult spinal cord. Journal of Neuroscience 22, 7097–7110.PubMedGoogle Scholar
  10. Bartsch, U., Bandtlow, C. E., Schnell, L., Bartsch, S., Spillmann, A. A., Rubin, B. P., Hillenbrand, R., Montag, D., Schwab, M. E. & Schachner, M. (1995) Lack of evidence that myelin-associated glycoprotein is a major inhibitor of axonal regeneration in the CNS. Neuron 15, 1375–1381.PubMedGoogle Scholar
  11. Bateman, A., Birney, E., Cerruti, L., Durbin, R., Etwiller, L., Eddy, S. R., Griffiths-Jones, S., Howe, K.L., Marshall, M. & Sonnhammer, E. L. (2002) The Pfam protein families database. Nucleic Acids Research 30, 276–280.PubMedGoogle Scholar
  12. Bergles, D. E., Roberts, J. D., Somogyi, P. & Jahr, C. E. (2000) Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 40, 187–191.Google Scholar
  13. Berry, M. (1982) Post-injury myelin-breakdown products inhibit axonal growth: An hypothesis to explain the failure of axonal regeneration in the mammalian central nervous system. Bibliotheca Anatomica 23, 1–11.Google Scholar
  14. Berry, M., Carlile, J. & Hunter, A. (1996) Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve. Journal of Neurocytology 25, 147–170.PubMedGoogle Scholar
  15. Bradbury, E. J., Khemani, S., King, V. R., Priestley, J. V. & Mcmahon, S. B. (1999) NT-3 promotes growth of lesioned adult rat sensory axons ascending in the dorsal columns of the spinal cord. European Journal of Neuroscience 11, 3873–3883.PubMedGoogle Scholar
  16. Bregman, B. S., Kunkel-Bagden, E., Schnell, L., Ning Dai, H., Gao, D. & Schwab, M. E. (1995) Recovery fromspinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378, 498–501.PubMedGoogle Scholar
  17. Bucher, P. & Bairoch, A. (1994) A generalized profile syntax for biomolecular sequences motifs and its function in automatic sequence interpretation. In ISMB-94; Proceedings 2nd International Conference on Intelligent Systems for Molecular Biology (edited by Altman, R., Brutlag, D., Karp, P., Lathrop, R. & Searls, D.) pp. 53–61. AAAI Press, Menlo Park.Google Scholar
  18. Buffo, A., Zagrebelsky, M., Huber, A. B., Skerra, A., Schwab, M. E., Strata, P. & Rossi, F. (2000) Application of neutralizing antibodies against NI-35/250 myelin-associated neurite growth inhibitory proteins to the adult rat cerebellum induces sprouting of uninjured Purkinje cell axons. Journal of Neuroscience 20, 2275–2286.PubMedGoogle Scholar
  19. Butt, A. M., Duncan, A., Hornby, M. F., Kirvell, S. L., Hunter, A., Levine, J. M. & Berry, M. (1999) Cells expressing the NG2 antigen contact nodes of Ranvier in adult CNS white matter. Glia 26, 84–91.PubMedGoogle Scholar
  20. Cadelli, D. & Schwab, M. E. (1991) Regeneration of lesioned septohippocampal acetylcholinesterase-positive axons is improved by antibodies against the myelinassociated neurite growth inhibitors NI-35/250. European Journal of Neuroscience 3, 825–832.PubMedGoogle Scholar
  21. Cai, D., Deng, K., Mellado, W., Lee, J., Ratan, R. & Filbin, M. (2002). Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth byMAGand myelin in vitro. Neuron 35, 711–719.PubMedGoogle Scholar
  22. Cai, D., Qiu, J., Cao, Z., Mcatee, M., Bregman, B. S. & Filbin, M. T. (2001) Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. Journal of Neuroscience 21, 4731–4739.PubMedGoogle Scholar
  23. Cai, D., Shen, Y., De Bellard, M., Tang, S. & Filbin, M. T. (1999) Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron 22, 89–101.PubMedGoogle Scholar
  24. Campbell, G., Anderson, P. N., Turmaine, M. & Lieberman, A. R. (1991) GAP-43 in the axons ofmammalian CNS neurons regenerating into peripheral nerve grafts. Experimental Brain Research 87, 67–74.Google Scholar
  25. Campbell, G., Holt, J. K. L., Shotton, H. R., Anderson, P. N., Bavetta, S. & Lieberman, A. R. (1999) Spontaneous regeneration after optic nerve injury in adult rat. NeuroReport 10, 3955–3960.PubMedGoogle Scholar
  26. Canning, D. R., Hoke, A., Malemud, C. J. & Silver, J. (1996) A potent inhibitor of neurite outgrowth that predominates in the extracellular matrix of reactive astrocytes. International Journal of Developmental Neuroscience 14, 153–175.PubMedGoogle Scholar
  27. Carenini, S., Montag, D., Cremer, H., Schachner, M. & Martini, R. (1997) Absence of the myelin-associated glycoprotein (MAG) and the neural cell adhesion molecule (N-CAM) interferes with the maintenance, but not with the formation of peripheral myelin. Cell and Tissue Research 287, 3–9.PubMedGoogle Scholar
  28. Caroni, P., Savio, T. & Schwab, M. E. (1988) Central nervous system regeneration: oligodendrocytes and myelin as non-permissive substrates for neurite growth. Progress in Brain Research 78, 363–370.PubMedGoogle Scholar
  29. Caroni, P. & Schwab, M. E. (1988a) Two membrane proteins fractions from rat central myelin with inhibitory properties for neurite outgrowth. Journal of Cell Biology 106, 1281–1288.PubMedGoogle Scholar
  30. Caroni, P. & Schwab, M. E. (1988b) Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1, 85–96.PubMedGoogle Scholar
  31. Castellani, V., Chedotal, A., Schachner, M., Faivre-Sarrailh, C. & Rougon, G. (2000). Analysis of the L1-deficient mouse phenotype reveals crosstalk between Sema3A and L1 signaling pathways in axonal guidance. Neuron 27, 237–249.PubMedGoogle Scholar
  32. Chaisuksunt, V., Zhang, Y., Anderson, P. N., Campbell, G., Vaudano, E., Schachner, M. & Lieberman A. R. (2000) Patterns of expression and distribution of mRNAs for L1, CHL1, c-jun and GAP-43 in identified regenerating neurons of the cerebellum and brainstem of the adult rat. Neuroscience 100, 87–108.PubMedGoogle Scholar
  33. Chen, M. S., Huber, A. B., van der Haar, M. E., Frank, M., Schnell, L., Spillmann, A. A., Christ, F. & Schwab M. E. (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434–439.PubMedGoogle Scholar
  34. Chong, M.-S., Woolf, C. J., Turmaine, M., Emson, P. C. & Anderson, P. N. (1996) Intrinsic vs extrinsic factors in determining the regeneration of the central processes of rat dorsal root ganglion neurons: the influence of a peripheral nerve graft. Journal of Comparative Neurology 370, 97–104.PubMedGoogle Scholar
  35. Davies, S. J., Fitch, M. T., Memberg, S. P., Hall, A. K., Raisman, G. & Silver, J. (1997) Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390, 680–683.PubMedGoogle Scholar
  36. Davies, S. J. A., Goucher, D. R., Doller, C. & Silver, J. (1999) Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. Journal of Neuroscience 19, 5810–5822.PubMedGoogle Scholar
  37. Dechant, G. & Barde, Y. A. (2002). The neurotrophin receptor p75(NTR): Novel functions and implications for diseases of the nervous system. Nature Neuroscience 5, 1131–1136.PubMedGoogle Scholar
  38. Dergham, P., Ellezam, B., Essagian, C., Avedissian, H., Lubell, W. D. & Mckerracher, L. (2002). Rho signaling pathway targeted to promote spinal cord repair. Journal of Neuroscience 22, 6570–6577.PubMedGoogle Scholar
  39. D'Eustachio, P., Colman, D. R. & Salzer, J. L. (1988). Chromosomal location of the mouse gene that encodes the myelin-associated glycoproteins. Journal of Neurochemistry 50, 589–593.PubMedGoogle Scholar
  40. Ding, J., Hu, B., Tang, L. S. & Yip, H. K. (2001). Study of the role of the low-affinity neurotrophin receptor p75 in naturally occurring cell death during development of the rat retina. Developmental Neuroscience 23, 390–398.PubMedGoogle Scholar
  41. Domeniconi, M. Cao, Z., Spencer, T., Sivasankaran, R., Wang, K., Nikulina, E., Kimura, N., Cai, H., Deng, K., Gao, Y., He, Z. & Filbin M. (2002) Myelin-associated glycoprotein interacts with the nogo66 receptor to inhibit neurite outgrowth. Neuron 35, 283–290.PubMedGoogle Scholar
  42. Dou, C. L. & Levine, J. M. (1994) Inhibition of neurite growth by the NG2 chondroitin sulfate proteoglycan. Journal of Neuroscience 14, 7616–7628.PubMedGoogle Scholar
  43. Falquet, L., Pagni, M., Bucher, P., Hulo, N., Sigrist, C. J., Hofmann, K. & Bairoch, A. (2002) The PROSITE database, its status in 2002. Nucleic Acids Research 30, 235–238.PubMedGoogle Scholar
  44. Fawcett, J. W. & Asher, R. A. (1999) The glial scar and central nervous system repair. Brain Research Bulletin 49, 377–391.PubMedGoogle Scholar
  45. Fishman, P. S. & Kelley, J. P. (1984) The fate of severed corticospinal axons. Neurology 34, 1161–1167.PubMedGoogle Scholar
  46. Fournier, A. E., Gould, G. C., Liu, B. P. & Strittmatter, S. M. (2002) Truncated soluble Nogo receptor binds Nogo-66 and blocks inhibition of axon growth by myelin. Journal of Neuroscience 22, 8876–8883.PubMedGoogle Scholar
  47. Fournier, A. E., Grandpre, T. & Strittmatter, S. M. (2001) Identification of a receptor mediating nogo-66 inhibition of axonal regeneration. Nature 409, 341–346.PubMedGoogle Scholar
  48. Fruttiger, M., Montag, D., Schachner, M. & Martini, R. (1995) Crucial role for the myelinassociated glycoprotein in the maintenance of axonmyelin integrity. European Journal of Neuroscience 7, 511–515.PubMedGoogle Scholar
  49. Fujita, N., Kemper, A., Dupree, J., Nakayasu, H., Bartsch, U., Schachner, M., Maeda, N., Suzuki, K. & Popko, B. (1998) The cytoplasmic domain of the large myelin-associated glycoprotein isoform is needed for proper CNS but not peripheral nervous system myelination. Journal of Neuroscience 18, 1970–1978.PubMedGoogle Scholar
  50. Gard, A. L., Maughon, R. H. & Schachner, M. (1996) In vitro oligodendrogliotrophic properties of cell adhesion molecules in the immunoglobulin superfamily: Myelin-associated glycoprotein and N-CAM. Journal of Neuroscience Research 46, 415–426.PubMedGoogle Scholar
  51. Gerin, C., Becquet, D. & Privat, A. (1995) Direct evidence for the link between monoaminergic descending pathways and motor activity. I.Astudy with microdialysis probes implanted in the ventral funiculus of the spinal cord. Brain Research 704, 191–201.PubMedGoogle Scholar
  52. Giehl, K. M. (2001). Trophic dependencies of rodent corticospinal neurons. Reviews in the Neurosciences 12, 79–94.PubMedGoogle Scholar
  53. Gorgels, T. G., de Kort, E. J., van Aanholt, H. T. & Nieuwenhuys, R. (1989) A quantitative analysis of the development of the pyramidal tract in the cervical spinal cord in the rat. Anatomy and Embryology (Berl) 179, 377–385.PubMedGoogle Scholar
  54. Grandpre, T., Li, S. & Strittmatter, S. M. (2002) Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417, 547–551.PubMedGoogle Scholar
  55. Grandpre, T., Nakamura, F., Vartanian, T. & Strittmatter, S. M. (2000) Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403, 439–444.PubMedGoogle Scholar
  56. Guillery, R. W. & Walsh, C. (1987) Changing glial organization relates to changing fiber order in the developing optic nerve of ferrets. Journal of Comparative Neurology 265, 203–217.PubMedGoogle Scholar
  57. Gupta, R. Jung, E. & Brunak, S. (2002) Prediction of N-glycosylation sites in human proteins. In preparation, web address: Scholar
  58. Habib, A. A., Gulcher, J. R., Hognason, T., Zheng, L. & Stefansson, K. (1998a) The omgp gene, a second growth suppressor within the NF1 gene. Oncogene 16, 1525–1531.PubMedGoogle Scholar
  59. Habib, A. A., Marton, L. S., Allwardt, B., Gulcher, J. R., Mikol, D. D., Hognason, T., Chattopadhyay, N. & Stefansson, K. (1998b) Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system. Journal of Neurochemistry 70, 1704–1711.PubMedGoogle Scholar
  60. Hains, B. C., Johnson, K. M., Mcadoo, D. J., Eaton, M. J. & Hulsebosch, C. E. (2001) Engraftment of serotonergic precursors enhances locomotor function and attenuates chronic central pain behavior following spinal hemisection injury in the rat. Experimental Neurology 171, 361–378.PubMedGoogle Scholar
  61. Hansen, J. E., Lund, O., Engelbrecht, J., Bohr, H., Nielsen, J. O. & Hansen, J. E. (1995) Prediction of O-glycosylation of mammalian proteins: specificity patterns of UDP-GalNAc: Polypeptide Nacetylgalactosaminyltransferase. Biochemical Journal, 308, 801–813.PubMedGoogle Scholar
  62. Hansen, J. E., Lund, O., Rapacki, K. & Brunak, S. (1997) O-GLYCBASE version 2.0: A revised database of O-glycosylated proteins. Nucleic Acids Research 25, 278–282.PubMedGoogle Scholar
  63. Hansen, J. E., Lund, O., Tolstrup, N., Gooley, A. A., Williams, K. L. & Brunak, S. (1998) NetOglyc: prediction of mucin type O-glycosylation sites based on sequence context and surface accessibility. Glycoconjugate Journal 15, 115–130.PubMedGoogle Scholar
  64. Hirsch, S., Labes, M. & Bahr, M. (2000). Changes in BDNF and neurotrophin receptor expression in degenerating and regenerating rat retinal ganglion cells. Restorative Neurology & Neuroscience 17, 125–134.Google Scholar
  65. Hofmann, K. & Stoffel, W. (1993) TMbase–A database of membrane spanning proteins segments. Biological Chemistry Hoppe-Seyler 374, 166.Google Scholar
  66. Houle, J. D. & Jin, Y. (2001) Chronically injured supraspinal neurons exhibit only modest axonal dieback in response to a cervical hemisection lesion. Experimental Neurology 169, 208–217.PubMedGoogle Scholar
  67. Hu, W. H., Hausmann, O. N., Yan, M. S., Walters, W. M., Wong, P. K. & Bethea, J. R. (2002) Identification and characterization of a novel Nogo-interacting mitochondrial protein (NIMP). Journal of Neurochemistry 81, 36–45.PubMedGoogle Scholar
  68. Huber, A. B., Weinmann, O., Brosamle, C., Oertle, T. & Schwab, M. E. (2002) Patterns ofNogo mRNA and protein expression in the developing and adult rat and after CNS lesions. Journal of Neuroscience 22, 3553–3567.PubMedGoogle Scholar
  69. Hunt, D., Mason, M. R. J., Campbell, G., Coffin, R. S. & Anderson, P. N. (2002) Nogo receptor mRNA expression in intact and regenerating CNS neurons. Molecular and Cellular Neuroscience 20, 537–552.PubMedGoogle Scholar
  70. Ivins, J. K. & Pittman, R. N. (1989) Growth cone-growth cone interactions in cultures of rat sympathetic neurons. Developmental Biology 135, 147–157.PubMedGoogle Scholar
  71. Jones, L. L., Yamaguchi, Y., Stallcup, W. B. & Tuszynski, M. H. (2002) NG2 is a major chondroitin sulfate proteoglycan produced after spinal cord injury and is expressed by macrophages and oligodendrocyte progenitors. Journal of Neuroscience 22, 2792–2803.PubMedGoogle Scholar
  72. Joosten, E. A., Gribnau, A. A. & Dederen, P. J. (1989) Postnatal development of the corticospinal tract in the rat. An ultrastructural anterograde HRP study. Anatomy and Embryology (Berl) 179, 449–456.Google Scholar
  73. Josephson, A., Trifunovski, A., Widmer, H. R., Widenfalk, J., Olson, L. & Spenger, C. (2002). Nogo-receptor gene activity: Cellular localization and developmental regulation of mRNA in mice and humans. Journal of Comparative Neurology 453, 292–304.PubMedGoogle Scholar
  74. Josephson, A., Widenfalk, J., Widmer, H. W., Olson, L. & Spenger, C. (2001) NOGO mRNA expression in adult and fetal human and rat nervous tissue and in weight drop injury. Experimental Neurology 169, 319–328.PubMedGoogle Scholar
  75. Kapfhammer, J. P. & Raper, J. A. (1987) Collapse of growth cone structure on contact with specific neurites in culture. Journal of Neuroscience 7, 201–212.PubMedGoogle Scholar
  76. Kartje, G. L., Schulz, M. K., Lopez-Yunez, A., Schnell, L. & Schwab, M. E. (1999) Corticostriatal plasticity is restricted by myelin-associated neurite growth inhibitors in the adult rat. Annals of Neurology 45, 778–786.PubMedGoogle Scholar
  77. Kay, B. K., Williamson, M. P. & Sudol, M. (2000) The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains. FASEB Journal 14, 231–241.PubMedGoogle Scholar
  78. Kottis, V., Thibault, P., Mikol, D., Xiao, Z. C., Zhang, R., Dergham, P. & Braun, P. E. (2002) Oligodendrocyte-myelin glycoprotein (OMgp) is an inhibitor of neurite outgrowth. Journal of Neurochemistry 82, 1566–1569.PubMedGoogle Scholar
  79. Lee, S. K. & Wolfe, S. W. (2000). Peripheral nerve injury and repair. Journal of the American Academy of Orthopaedic Surgeons 8, 243–252.PubMedGoogle Scholar
  80. Lehmann, M., Fournier, A., Selles-Navarro, I., Dergham, P., Sebok, A., Leclerc, N., Tigyi, G. & Mckerracher, L. (1999) Inactivation of Rho signaling pathway promotes CNS axon regeneration. Journal of Neuroscience 19, 7537–7547.PubMedGoogle Scholar
  81. Letunic, I., Goodstadt, L., Dickens, N. J., Doerks, T., Schultz, J., Mott, R., Ciccarelli, F., Copley, R. R., Ponting, C. P. & Bork, P. (2002) Recent improvements to the SMART domainbased sequence annotation resource. Nucleic Acids Research 30, 242–244.PubMedGoogle Scholar
  82. Li, M., Shibata, A., Li, C., Braun, P. E., Mckerracher, L., Roder, J., Kater S. B. & David, S. (1996) Myelin-associated glycoprotein inhibits neurite/axon growth and causes growth cone collapse. Journal of Neuroscience Research 46, 404–414.PubMedGoogle Scholar
  83. Li, Q., Qi, B., Oka, K., Shimakage, M., Yoshioka, N., Inoue, H., Hakura, A., Kodama, K., Stanbridge, E. J. & Yutsudo, M. (2001) Link of a new type of apoptosis-inducing gene ASY/Nogo-B to human cancer. Oncogene 20, 3929–3936.PubMedGoogle Scholar
  84. Liu, B. P., Fournier, A., Grandpre, T. & Strittmatter, S. M. (2002a) Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 297, 1190–1193.PubMedGoogle Scholar
  85. Liu, H., Ng, C. E. & Tang, B. L. (2002b) Nogo-A expression in mouse central nervous system neurons. Neuroscience Letters 328, 257–260.PubMedGoogle Scholar
  86. Liu, R. Y., Schmid, R. S., Snider, W. D. & Maness, P. F. (2002c) NGF enhances sensory axon growth induced by laminin but not by the L1 cell adhesion molecule. Molecular and Cellular Neuroscience 20, 2–12.PubMedGoogle Scholar
  87. Low, K., Orberger, G., Schmitz, B., Martini, R. & Schachner, M. (1994) The L2/HNK-1 carbohydrate is carried by the myelin associated glycoprotein and sulphated glucuronyl glycolipids in muscle but not cutaneous nerves of adult mice. European Journal of Neuroscience 6, 1773–1781.PubMedGoogle Scholar
  88. Lutjens, R., Igarashi, M., Pellier, V., Blasey, H., di Paolo, G., Ruchti, E., Pfulg, C., Staple, J. K., Catsicas, S. & Grenningloh, G. (2000) Localization and targeting of SCG10 to the trans-Golgi apparatus and growth cone vesicles. European Journal of Neuroscience 12, 2224–2234.PubMedGoogle Scholar
  89. Marcus, J., Dupree, J. L. & Popko, B. (2002) Myelinassociated glycoprotein and myelin galactolipids stabilize developing axo-glial interactions. Journal of Cell Biology 156, 567–577.PubMedGoogle Scholar
  90. Martini, R. (1994) Expression and functional roles of neural cell surface molecules and extracellular matrix components during development and regeneration of peripheral nerves. Journal of Neurocytology 23, 1–28.PubMedGoogle Scholar
  91. Martini, R., Schachner, M. & Brushart, T. M. (1994) The L2/HNK-1 carbohydrate is preferentially expressed by previously motor axon-associated Schwann cells in reinnervated peripheral nerves. Journal of Neuroscience 14, 7180–7191.PubMedGoogle Scholar
  92. Martini, R., Xin, Y., Schmitz, B. & Schachner, M. (1992) The L2/HNK-1 carbohydrate epitope is involved in the preferential outgrowth of motor neurons on ventral roots and motor nerves. European Journal of Neuroscience 4, 628–639.PubMedGoogle Scholar
  93. Mason, M. R. J., Lieberman, A. R., Grenningloh, G. & Anderson, P. N. (2002) Transcriptional control of SCG10 and CAP-23 is correlated with the regeneration of the axons of peripheral and central neurons in vivo. Molecular and Cellular Neuroscience 20, 595–615.PubMedGoogle Scholar
  94. Mckerracher, L. (2002) Ganglioside rafts asMAGreceptors that mediate blockade of axon growth. Proceedings of the National Academy of Sciences USA 99, 7811–7813.Google Scholar
  95. Mckerracher, L., David, S., Jackson, D. L., Kottis, V., Dunn, R. J. & Braun, P. E. (1994). Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805–811.PubMedGoogle Scholar
  96. Miescher, G. C., Lutzelschwab, R., Erne, B., Ferracin, F., Huber, S. & Steck, A. J. (1997) Reciprocal expression of myelin-associated glycoprotein splice variants in the adult human peripheral and central nervous systems. Molecular Brain Research 52, 299–306.PubMedGoogle Scholar
  97. Mikol, D. D. & Stefansson, K. (1988) A phosphatidylinositol-linked peanut agglutinin-binding glycoprotein in central nervous system myelin and on oligodendrocytes. European Journal of Cell Biology 106, 1273–1279.Google Scholar
  98. Mikol, D. D., Gulcher, J. R. & Stefansson, K. (1990). The oligodendrocyte-myelin glycoprotein belongs to a distinct family of proteins and contains the HNK-1 carbohydrate. Journal of Cell Biology 110, 471–479.PubMedGoogle Scholar
  99. Morrow, D. R., Campbell, G., Lieberman, A. R. & Anderson, P. N. (1993) Differential regenerative growth of CNS axons into tibial and peroneal nerve grafts in the thalamus of adult rats. Experimental Neurology 120, 60–69.PubMedGoogle Scholar
  100. Mukhopadhyay, G., Doherty, P., Walsh, F. S., Crocker, P. R. & Filbin, M. T. (1994). A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron 13, 757–767.PubMedGoogle Scholar
  101. Niederost, B., Oertle, T., Fritsche, J., Mckinney, R. A., & Bandtlow, C. E. (2002). Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1. Journal of Neuroscience 22, 10368–10376.PubMedGoogle Scholar
  102. Nielsen, H., Engelbrecht, J., Brunak, S. & von Heijne, G. (1997). Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Protein Engineering 10, 1–6.Google Scholar
  103. Nishimar, U. H., Takizawa, H. & Kudo, N. (2000) 5-Hydroxytryptamine-induced locomotor rhythm in the neonatal mouse spinal cord in vitro. Neuroscience Letters 280, 187–190.PubMedGoogle Scholar
  104. Oertle, T., Huber, C., van Der, P. H. & Schwab, M. E. (2003). Genomic structure and functional characterisation of the promoters of human and mouse nogo/rtn4. Journal of Molecular Biology 325, 299–323.PubMedGoogle Scholar
  105. Oudega, M., Rosano, C., Sadi, D., Wood, P. M., Schwab, M. E. & Hagg, T. (2000) Neutralizing antibodies against neurite growth inhibitor NI-35/250 do not promote regeneration of sensory axons in the adult rat spinal cord. Neuroscience 100, 873–883.PubMedGoogle Scholar
  106. Pasterkamp, R. J., Anderson, P. N. & Verhaagen, J. (2001) Peripheral nerve injury fails to induce growth of lesioned ascending dorsal column axons into spinal cord scar tissue expressing the axon repellent Semaphorin3A. European Journal of Neuroscience 13, 457–471.PubMedGoogle Scholar
  107. Pedraza, L., Frey, A. B., Hempstead, B. L., Colman, D. R. & Salzer, J. L. (1991) Differential expression of MAG isoforms during development. Journal of Neuroscience Research 29, 141–148.PubMedGoogle Scholar
  108. Pot, C., Simonen, M., Weinmann, O., Schnell, L., Christ, F., Stoeckle, S., Berger, P., Rulicke, T., Suter, U. & Schwab, M. E. (2002). Nogo-A expressed in Schwann cells impairs axonal regeneration after peripheral nerve injury. Journal of Cell Biology 159, 29–35.PubMedGoogle Scholar
  109. Prinjha, R. K., Hill, C., Roberts, E., Irving, J., Campbell, C., Parsons, A., Davis, R., Morrow, R., Woodhams, P. L., Philpott, K. L., Pangalos, M. & Walsh, F. S. (2002) Mapping the functional inhibitory sites of Nogo-A. Discovery of regulated expression following neuronal injury. Program No. 333.12 2002 Abstracts viewer/Itinerary planner. Washington, DC: Society for Neuroscience, 2002. CD-ROM.Google Scholar
  110. Prinjha, R., Moore, S. E., Vinson, M., Blake, S., Morrow, R., Christie, G., Michalovich, D., Simmons, D. L. & Walsh, F. S. (2000) Inhibitor of neurite outgrowth in humans. Nature 403, 383–384.PubMedGoogle Scholar
  111. Raineteau, O., Z'Graggen, W. J., Thallmair, M. & Schwab, M. E. (1999). Sprouting and regeneration after pyramidotomy and blockade of the myelinassociated neurite growth inhibitors NI 35/250 in adult rats. European Journal of Neuroscience 11, 1486–1490.PubMedGoogle Scholar
  112. Ramon y Cajal, S. (1959) Degeneration and Regeneration of the Nervous System. New York: Hafner Publishing Company.Google Scholar
  113. Richardson, P. M., Issa, V. M. & Aguayo, A. J. (1984). Regeneration of long spinal axons in the rat. Journal of Neurocytology 13, 165–182.PubMedGoogle Scholar
  114. Richardson, P. M. & Verge, V. M. K. (1986). The induction of a regenerative propensity in sensory neurons following peripheral axonal injury. Journal of Neurocytology 15, 585–594.PubMedGoogle Scholar
  115. Rossi, F., Buffo, A. & Strata, P. (2001) Regulation of intrinsic regenerative properties and axonal plasticity in cerebellar Purkinje cells. Restorative Neurology & Neuroscience 19, 85–94.Google Scholar
  116. Rubin, B. P., Dusart, I. & Schwab, M. E. (1994). A monoclonal antibody (IN-1) which neutralizes neurite growth inhibitory proteins in the rat CNS recognizes antigens localized in CNS myelin. Journal of Neurocytology 23, 209–217.PubMedGoogle Scholar
  117. Salzer, J. L., Holmes, W. P. & Colman, D. R. (1987). The amino acid sequences of the myelin-associated glycoproteins: homology to the immunoglobulin gene superfamily. Journal of Cell Biology 104, 957–965.PubMedGoogle Scholar
  118. Schafer, M., Fruttiger, M., Montag, D., Schachner, M. & Martini, R. (1996) Disruption of the gene for the myelin-associated glycoprotein improves axonal regrowth along myelin in C57BL/Wlds mice. Neuron 16, 1107–1113.PubMedGoogle Scholar
  119. Schnell, L., Schneider, R., Kolbeck, R., Barde, Y.-A. & Schwab, M. E. (1994) Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367, 170–173.PubMedGoogle Scholar
  120. Schnell, L. & Schwab, M. E. (1990) Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343, 269–272.PubMedGoogle Scholar
  121. Schnell, L. & Schwab, M. E. (1993) Sprouting and regeneration of lesioned corticospinal tract fibres in the adult rat spinal cord. European Journal of Neuroscience 5, 1156–1171.PubMedGoogle Scholar
  122. Schultz, J., Milpetz, F., Bork, P. & Ponting, C. P. (1998) SMART, a simple modular architecture research tool: identification of signalling domains. Proceedings of the National Academy of Sciences USA 95, 5857–5864.Google Scholar
  123. Schwab, M. E. (1996) Molecules inhibiting neurite growth: A minireview. Neurochemical Research 21, 755–761.PubMedGoogle Scholar
  124. Schwab, M. E. & Caroni, P. (1988) Oligodendrocytes and CNS myelin are nonpermissive substrates for neurite growth and fibroblast spreading in vitro. Journal of Neuroscience 8, 2381–2393.PubMedGoogle Scholar
  125. Servant, F., Bru, C., Carrere, S., Courcelle, E., Gouzy, J., Peyruc, D. & Kahn, D. (2002). ProDom: Automated clustering of homologous domains. Briefings in Bioinformatics 3, 246–251.PubMedGoogle Scholar
  126. Sheedlo, H. J., Srinivasan, B., Marie Brunzinkernagel, A., Roque, C. H., Lambert, W., Wordinger, R. J. & Roque, R. S. (2002). Expression of p75(NTR) in photoreceptor cells of dystrophic rat retinas. Molecular Brain Research 103, 71–79.PubMedGoogle Scholar
  127. Shimizu-Okabe, C., Matsuda, Y., Koito, H. & Yoshida, S. (2001) L-isoform but not S-isoform of myelin associated glycoprotein promotes neurite outgrowth of mouse cerebellar neurons. Neuroscience Letters 311, 203–205.PubMedGoogle Scholar
  128. Skene, J. H. & Willard, M. (1981) Axonally transported proteins associated with axon growth in rabbit central and peripheral nervous systems. Journal of Cell Biology 89, 96–103.PubMedGoogle Scholar
  129. Slawinska, U., Majczynski, H. & Djavadian, R. (2000) Recovery of hindlimb motor functions after spinal cord transection is enhanced by grafts of the embryonic raphe nuclei. Experimental Brain Research 132, 27–38.Google Scholar
  130. Spillmann, A. A., Bandtlow, C. E., Lottspeich, F., Keller, F. & Schwab, M. E. (1998) Identification and characterization of a bovine neurite growth inhibitor (bNI-220). Journal of Biological Chemistry 273, 19283–19293.PubMedGoogle Scholar
  131. Tang, S., Qiu, J., Nikulina, E., & Filbin, M. T. (2001). Soluble myelin-associated glycoprotein released fromdamagedwhite matter inhibits axonal regeneration. Molecular & Cellular Neuroscience 18, 259–269.Google Scholar
  132. Tatagiba, M., Rosahl, S., Gharabaghi, A., Blomer, U., Brandis, A., Skerra, A., Samii, M., & Schwab, M. E. (2002). Regeneration of auditory nerve following complete sectioning and intrathecal application of the IN-1 antibody. Acta Neurochirurgica 144, 181–187.PubMedGoogle Scholar
  133. Thompson, J. D., Higgins, D. G. & Gibson, T. J. (1994). CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Research 22, 4673–4680.PubMedGoogle Scholar
  134. Tozaki, H., Kawasaki, T., Takagi, Y. & Hirata, T. (2002) Expression ofNogoprotein by growing axons in the developing nervous system. Molecular Brain Research 104, 111–119.PubMedGoogle Scholar
  135. Turnley, A. M. & Bartlett, P. F. (1998) MAG and MOG enhance neurite outgrowth of embryonic mouse spinal cord neurons. NeuroReport 9, 1987–1990.PubMedGoogle Scholar
  136. Vaudano, E., Campbell, G., Anderson, P. N., Davies, A. P., Woolhead, C., Schreyer, D. J. & Lieberman, A. R. (1995) The effects of a lesion or a peripheral nerve graft on GAP-43 upregulation in the adult rat brain: an in situ hybridization and immunocytochemical study. Journal of Neuroscience 15, 3594–3611.PubMedGoogle Scholar
  137. Vaudano, E, Campbell, G, Hunt, S. P. & Lieberman, A. R. (1998). Axonal injury and peripheral nerve grafting in the thalamus and cerebellum of the adult rat: upregulation of c-jun and correlation with regenerative potential. European Journal of Neurocience 10, 2644–2656.Google Scholar
  138. Verge, V. M., Merlio, J. P., Grondin, J., Ernfors, P., Persson, H., Riopelle, R. J., Hokfelt, T. & Richardson, P. M. (1992). Colocalization of NGF binding sites, trk mRNA, and low-affinity NGF receptor mRNA in primary sensory neurons: responses to injury and infusion of NGF. Journal of Neuroscience 12, 4011–4022.PubMedGoogle Scholar
  139. Vinson, M., Strijbos, P. J., Rowles, A., Facci, L., Moore, S. E., Simmons, D. L. & Walsh, F. S. (2001) Myelin-associated glycoprotein interacts with ganglioside gt1b. a mechanism for neurite outgrowth inhibition. Journal of Biological Chemistry 276, 20280–20285.PubMedGoogle Scholar
  140. Viskochil, D., Cawthon, R., O'Connell, P., Xu, G. F., Stevens. J., Culver, M., Carey, J. & White, R. (1991) The gene encoding the oligodendrocyte-myelin glycoprotein is embedded within the neurofibromatosis type 1 gene. Molecular and Cellular Biology 11, 906–912.PubMedGoogle Scholar
  141. Vyas, A. A., Patel, H. V., Fromholt, S. E., Hefferlauc, M., Vyas, K. A., Dang, J., Schachner, M. & Schnaar, R. L. (2002) Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration. Proceedings of the National Academy of Sciences USA 99, 8412–8417.Google Scholar
  142. Walsh, G. S., Krol, K. M., Crutcher, K. A. & Kawaja, M. D. (1999). Enhanced neurotrophininduced axon growth in myelinated portions of the CNS in mice lacking the p75 neurotrophin receptor. Journal of Neuroscience 19, 4155–4168.PubMedGoogle Scholar
  143. Wang, X., Chun, S. J., Treloar, H., Vartanian, T., Greer, C. A. & Strittmatter, S. M. (2002a) Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact. Journal of Neuroscience 22, 5505–5515.PubMedGoogle Scholar
  144. Wang, K. C., Kim, J. A., Sivasankaran, R., Segal, R. & He, Z. (2002b). p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78.PubMedGoogle Scholar
  145. Wang, K. C., Koprivica, V., Kim, J. A., Sivasankaran, R., Guo, Y., Neve, R. L. & He, Z. (2002c) Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944.PubMedGoogle Scholar
  146. Weibel, D., Cadelli, D. & Schwab, M. E. (1994) Regeneration of lesioned rat optic nerve fibers is improved after neutralization of myelin-associated neurite growth inhibitors. Brain Research 642, 259–266.PubMedGoogle Scholar
  147. Williams, R. W., Borodkin, M. & Rakic, P. (1991) Growth cone distribution patterns in the optic nerve of fetal monkeys: implications for mechanisms of axon guidance. Journal of Neuroscience 11, 1081–1094.PubMedGoogle Scholar
  148. Wong, S. T., Henley, J. R., Kanning, K. C., Huang, K. H., Bothwell, M. & Poo, M. M. (2002). A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nature Neuroscience 5, 1302–1308.PubMedGoogle Scholar
  149. Yamashita, T., Higuchi, H. & Tohyama, M. (2002) The p75 receptor transduces the signal from myelinassociated glycoprotein to Rho. Journal of Cell Biology 157, 565–570.PubMedGoogle Scholar
  150. Yamashita, T., Tucker, K. L. & Barde, Y. A. (1999). Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24, 585–593.PubMedGoogle Scholar
  151. Yang, J., Yu, L., Bi, A. D. & Zhao, S. Y. (2000) Assignment of the human reticulon 4 gene (RTN4) to chromosome 2p14—>2p13 by radiation hybrid mapping. Cytogenetics and Cell Genetics 88, 101–102.PubMedGoogle Scholar
  152. Zagrebelsky, M., Buffo, A., Skerra, A., Schwab, M. E., Strata, P. & Rossi, F. (1998) Retrograde regulation of growth-associated gene expression in adult rat Purkinje cells by myelin-associated neurite growth inhibitory proteins. Journal of Neuroscience 18, 7912–7929.PubMedGoogle Scholar
  153. Zdobnov, E. M. & Apweiler, R. (2001). InterProScan–an integration platform for the signaturerecognition methods in InterPro. Bioinformatics 17, 847–848.PubMedGoogle Scholar
  154. Z'Graggen, W. J., Metz, G. A., Kartje, G. L., Thallmair, M. & Schwab, M. E. (1998). Functional recovery and enhanced corticofugal plasticity after unilateral pyramidal tract lesion and blockade of myelinassociated neurite growth inhibitors in adult rats. Journal of Neuroscience 18, 4744–4757.Google Scholar
  155. Zhang, Y., Dijkhuizen, P. A., Anderson, P. N., Lieberman, A. R. & Verhaagen, J. (1998) NT-3 delivered by an adenoviral vector induces injured dorsal root axons to regenerate back into the spinal cord. Journal of Neuroscience Research 54, 554–562.PubMedGoogle Scholar
  156. Zhang, Y., Tohyama, K., Winterbottom, J. K., Haque, N. S., Schachner, M., Lieberman, A. R. & Anderson, P. N. (2001) Correlation between putative inhibitory molecules at the dorsal root entry zone and failure of dorsal root axonal regeneration. Molecular and Cellular Neuroscience 17, 444–459.PubMedGoogle Scholar
  157. Zhang, Y., Winterbottom, J. K., Schachner, M., Lieberman, A. R. & Anderson, P. N. (1997) Tenascin-C expression and axonal sprouting following injury to the spinal dorsal columns in the adult rat. Journal of Neuroscience Research 49, 433–450.PubMedGoogle Scholar
  158. Zhou, Z. M., Sha, J. H., Li, J. M., Lin, M., Zhu, H., Zhou, Y. D., Wang, L. R., Zhu, H., Wang, Y. Q. & Zhou, K. Y. (2002) Expression of a novel reticulonlike gene in human testis. Reproduction 123, 227–234.PubMedGoogle Scholar
  159. Zuo, J., Hernandez, Y. J. & Muir, D. (1998) Chondroitin sulfate proteoglycan with neurite-inhibiting activity is up-regulated following peripheral nerve injury. Journal of Neurobiology 34, 41–54.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • D. Hunt
    • 1
    • 2
  • R.S. Coffin
    • 1
  • P.N. Anderson
    • 2
  1. 1.Department of Immunology and Molecular Pathology, The Windeyer InstituteUniversity College LondonLondonUK;
  2. 2.Department of Anatomy and Developmental BiologyUniversity College LondonLondonUK

Personalised recommendations