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Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration

Nature volume 409, pages 341–346 (2001)Cite this article

Abstract

Nogo has been identified as a component of the central nervous system (CNS) myelin that prevents axonal regeneration in the adult vertebrate CNS. Analysis of Nogo-A has shown that an axon-inhibiting domain of 66 amino acids is expressed at the extracellular surface and at the endoplasmic reticulum lumen of transfected cells and oligodendrocytes1. The acidic amino terminus of Nogo-A is detected at the cytosolic face of cellular membranes1 and may contribute to inhibition of axon regeneration at sites of oligodendrocyte injury2,3. Here we show that the extracellular domain of Nogo (Nogo-66) inhibits axonal extension, but does not alter non-neuronal cell morphology. In contrast, a multivalent form of the N terminus of Nogo-A affects the morphology of both neurons and other cell types. Here we identify a brain-specific, leucine-rich-repeat protein with high affinity for soluble Nogo-66. Cleavage of the Nogo-66 receptor and other glycophosphatidylinositol-linked proteins from axonal surfaces renders neurons insensitive to Nogo-66. Nogo-66 receptor expression is sufficient to impart Nogo-66 axonal inhibition to unresponsive neurons. Disruption of the interaction between Nogo-66 and its receptor provides the potential for enhanced recovery after human CNS injury.

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Figure 1: Comparison of Nogo domains.
Figure 2: Ligand-binding assay for axonal Nogo-66 receptors.
Figure 3: Nogo-66 binding to COS-7 cells expressing the Nogo-66 receptor.
Figure 4: Structure of Nogo-66 receptor.
Figure 5: Distribution of Nogo-66 receptor expression.
Figure 6: Nogo-66 receptor mediates growth-cone collapse by Nogo-66.

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Acknowledgements

This work was supported by grants to S.M.S. from the NIH and the Christopher Reeve Paralysis Foundation. A.F. was an FCAR research fellow. S.M.S. is an Investigator of the Patrick and Catherine Weldon Donaghue Medical Research Foundation.

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Author notes

  1. Alyson E. Fournier and Tadzia GrandPre: These authors contributed equally to this work

  2. Correspondence and requests for materials should be addressed to S.M.S. (e-mail: stephen.strittmatter@yale.edu). The mouse and human Nogo-66 receptor mRNA sequences are deposited in GenBank under accession numbers AF283462 and AF283463, respectively.

Authors and Affiliations

  1. Department of Neurology and Section of Neurobiology, Yale University School of Medicine, P.O. Box 208018, New Haven , 06520, Connecticut, USA

    Alyson E. Fournier, Tadzia GrandPre & Stephen M. Strittmatter

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  1. Alyson E. Fournier
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Fournier, A., GrandPre, T. & Strittmatter, S. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration . Nature 409, 341–346 (2001). https://doi.org/10.1038/35053072

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