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Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth

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Abstract

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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Acknowledgements

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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Competing interests

The authors declare that they have no competing financial interests.

Correspondence to Zhigang He.

Supplementary information

  1. Supplementary Information Figure 1 Legend (DOC 22 kb)

  2. Supplementary Information Figure 1 (JPG 128 kb)

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Further reading

Figure 1: GPI-anchored myelin component(s) induces growth cone collapse.
Figure 2: OMgp is a myelin-associated inhibitor.
Figure 3: The Nogo-66 receptor is an OMgp-binding protein.
Figure 4: NgR mediates OMgp-elicited growth cone collapse.

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