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Neogenin mediates the action of repulsive guidance molecule

Nature Cell Biology volume 6, pages 756–762 (2004)Cite this article

Abstract

Repulsive guidance molecule (RGM) is a recently identified protein implicated in both axonal guidance and neural tube closure1,2. The avoidance of chick RGM in the posterior optic tectum by growing temporal, but not nasal, retinal ganglion cell axons is thought to contribute to visual map formation. In contrast to ephrins, semaphorins, netrins and slits3,4, no receptor mechanism for RGM action has been defined. Here, an expression cloning strategy identified neogenin as a binding site for RGM, with a sub-nanomolar affinity. Consistent with selective axonal responsiveness to RGM, neogenin is expressed in a gradient across the chick retina. Neogenin is known to be one of several netrin-binding proteins5 but only neogenin interacts with RGM. The avoidance of RGM by temporal retinal axons is blocked by the anti-neogenin antibody and the soluble neogenin ectodomain. Dorsal root ganglion axons are unresponsive to RGM but are converted to a responsive state by neogenin expression. Thus, neogenin functions as an RGM receptor.

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Figure 1: Neogenin is a high affinity binding site for RGM.
Figure 2: Neogenin is expressed in a temporal–nasal gradient in the retina.
Figure 3: Neogenin is required for RGM inhibition of temporal retinal axons.
Figure 4: Neogenin expression is sufficient for DRG avoidance of RGM.

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Acknowledgements

We thank R. Nordin for technical assistance, R. Salie, V. Niederkofler and S. Arber for providing the mouse RGM-A–AP expression vector and Peter L. Jeffrey for anti-Thy-1 antibody. This work is supported by a grant from the National Institutes of Health to S.M.S and by a BioChance grant from the Bundesministerium für Bildung und Forschung to Migragen. S.M.S. is an investigator of the Patrick and Catherine Weldon Donaghue Medical Research Foundation. A.C. is supported by Retina France, the Schlumberger foundation and Association pour la Recherche sur le Cancer (ARC).

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  1. Srikanth Rajagopalan, Lutz Deitinghoff and Denise Davis: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06510, CT, USA

    Srikanth Rajagopalan, Denise Davis & Stephen M. Strittmatter

  2. Abbott GmbH & Co KG, Knollstrasse, 67061, Ludwigshafen, Germany

    Lutz Deitinghoff & Bernhard K. Mueller

  3. Department of Experimental Embryology, Tissue Engineering Division, Institute of Anatomy, Tübingen, D-72074, Germany

    Sabine Conrad & Thomas Skutella

  4. CNRS UMR 7102, Université Paris 6, 9 Quai Saint Bernard, Paris, 75005, France

    Alain Chedotal

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Correspondence to Stephen M. Strittmatter.

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Competing interests

The authors declare that two of the authors, Bernhard Mueller and Lutz Deitinghoff, were employed and supported by a commercial venture, Migragen AG, during the course of this work. Currently, both are employed by Abbott GmbH&CO.

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Rajagopalan, S., Deitinghoff, L., Davis, D. et al. Neogenin mediates the action of repulsive guidance molecule. Nat Cell Biol 6, 756–762 (2004). https://doi.org/10.1038/ncb1156

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