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Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1

Nature volume 401, pages 69–73 (1999)Cite this article

Abstract

Growing axons are guided by both diffusible and substrate-bound factors1,2,3. Growth cones of retinal neurons exhibit chemoattractive turning towards the diffusible factor netrin-1 in vitro4 and are guided into the optic nerve head (ONH) by localized netrin-1 (ref. 5). Here we report that, in Xenopus, laminin-1 from the extracellular matrix (ECM), converts netrin-mediated attraction into repulsion. A soluble peptide fragment of laminin-1 (YIGSR) mimics this laminin-induced conversion. Low levels of cyclic AMP in growth cones also lead to the conversion of netrin-induced attraction into repulsion6, and we show that the amount of cAMP decreases in the presence of laminin-1 or YIGSR, suggesting a possible mechanism for laminin's effect. At the netrin-1-rich ONH, where axons turn sharply to leave the eye, laminin-1 is confined to the retinal surface. Repulsion from the region in which laminin and netrin are coexpressed may help to drive axons into the region where only netrin is present, providing a mechanism for their escape from the retinal surface. Consistent with this idea, YIGSR peptides applied to the developing retina cause axons to be misdirected at the ONH. These findings indicate that ECM molecules not only promote axon outgrowth, but also modify the behaviour of growth cones in response to diffusible guidance cues.

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Figure 1: Laminin-1 converts netrin-1-induced growth-cone attraction into repulsion.
Figure 2: YIGSR mimics laminin-1 and causes repulsive turning in netrin-1 gradients.
Figure 3: Opposite netrin-1-induced turning behaviours of single growth cones with and without YIGSR peptide.
Figure 4: Laminin-1 and YIGSR reduce cAMP levels in retinal growth cones.
Figure 5: Exogenous YIGSR induces defects at the ONH where endogenous distribution of laminin-1 and netrin-1 is spatially discrete.

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Acknowledgements

We thank H. K. Kleinman, A. Wiemelt and J. Fawcett for peptides and antibodies, and B. Berninger, W. Harris, T. Gomez, S.-i. Ohnuma, B. Barres, S.-i. Nakagawa and T. Das for discussions. This work was supported by NIH, PEW Scholars Award and a MRC programme grant (C.H.) and NIH grants (M.-M.P., M.T.-L.).

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Author notes

  1. Veit H. Höpker and Derryck Shewan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, University of California at San Diego, La Jolla, 92093-0357, California, USA

    Veit H. Höpker & Mu-ming Poo

  2. Department of Anatomy, University of Cambridge, Cambridge, CB2 3DY, UK

    Derryck Shewan & Christine Holt

  3. Departments of Anatomy, Howard Hughes Medical Institute, and Biochemistry and Biophysics, University of California, San Francisco, 94143-0452, California, USA

    Marc Tessier-Lavigne

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Correspondence to Christine Holt.

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Höpker, V., Shewan, D., Tessier-Lavigne, M. et al. Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1. Nature 401, 69–73 (1999). https://doi.org/10.1038/43441

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