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Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein

Nature volume 403, pages 439–444 (2000)Cite this article

Abstract

Adult mammalian axon regeneration is generally successful in the peripheral nervous system (PNS) but is dismally poor in the central nervous system (CNS). However, many classes of CNS axons can extend for long distances in peripheral nerve grafts1. A comparison of myelin from the CNS and the PNS has revealed that CNS white matter is selectively inhibitory for axonal outgrowth2. Several components of CNS white matter, NI35, NI250(Nogo) and MAG, that have inhibitory activity for axon extension have been described3,4,5,6,7. The IN-1 antibody, which recognizes NI35 and NI250(Nogo), allows moderate degrees of axonal regeneration and functional recovery after spinal cord injury8,9. Here we identify Nogo as a member of the Reticulon family, Reticulon 4-A. Nogo is expressed by oligodendrocytes but not by Schwann cells, and associates primarily with the endoplasmic reticulum. A 66-residue lumenal/extracellular domain inhibits axonal extension and collapses dorsal root ganglion growth cones. In contrast to Nogo, Reticulon 1 and 3 are not expressed by oligodendrocytes, and the 66-residue lumenal/extracellular domains from Reticulon 1, 2 and 3 do not inhibit axonal regeneration. These data provide a molecular basis to assess the contribution of Nogo to the failure of axonal regeneration in the adult CNS.

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Figure 1: Identification of Nogo.
Figure 2: Topology of Nogo protein in transfected COS-7 cells.
Figure 3: Localization of Nogo mRNA to oligodendrocytes.
Figure 4: Nogo collapses axonal growth cones.
Figure 5: The lumenal/extracellular domain of Nogo inhibits neurite outgrowth.

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Acknowledgements

The authors thank A. Fournier for invaluable experimental advice and assistance. This work was supported by grants to S.M.S. from the NIH and the American Paralysis Association, and to F.N. from the Spinal Cord Research Fund of the Paralyzed Veterans of America. S.M.S. is an Investigator of the Patrick and Catherine Weldon Donaghue Medical Research Foundation.

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  1. Tadzia GrandPré, Fumio Nakamura and Stephen M. Strittmatter: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Neurology,

    Tadzia GrandPré, Fumio Nakamura & Stephen M. Strittmatter

  2. Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Stephen M. Strittmatter

  3. Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts, USA

    Timothy Vartanian

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  1. Tadzia GrandPré
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  2. Fumio Nakamura
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Correspondence to Stephen M. Strittmatter.

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GrandPré, T., Nakamura, F., Vartanian, T. et al. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403, 439–444 (2000). https://doi.org/10.1038/35000226

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