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Nature 386, 833 - 838 (24 April 1997); doi:10.1038/386833a0

Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors

E. David Leonardo*, Lindsay Hinck*, Masayuki Masu*, Kazuko Keino-Masu*, Susan L. Ackerman§ & Marc Tessier-Lavigne*

*Howard Hughes Medical Institute, Department of Anatomy, Programs in Cell and Developmental Biology and Neuroscience, University of California, San Francisco, California 94143-0452, USA
National Defense Medical College, Department of Physiology, Saitama 359, Japan
§The Jackson Laboratory, Bar Harbor, Maine 04609, USA
These authors contributed equally to this work

In the developing nervous system, migrating cells and axons are guided to their targets by cues in the extracellular environment. The netrins are a family of phylogenetically conserved guidance cues that can function as diffusible attractants and repellents for different classes of cells and axons1–10. In vertebrates, insects and nematodes, members of the DCC subfamily of the immunoglobulin superfamily have been implicated as receptors that are involved in migration towards netrin sources6,11–13,15. The mechanisms that direct migration away from netrin sources (presumed repulsions) are less well understood. In Caenorhabditis elegans, the transmembrane protein UNC-5 (ref. 14) has been implicated in these responses, as loss of unc-5 function causes migration defects16,17 and ectopic expression of unc-5 in some neurons can redirect their axons away from a netrin source18. Whether UNC-5 is a netrin receptor or simply an accessory to such a receptor has not, however, been defined. We now report the identification of two vertebrate homologues of UNC-5 which, with UNC-5 and the product of the mouse rostral cerebellar malformation gene (rcm)19, define a new subfamily of the immunoglobulin superfamily, and whose messenger RNAs show prominent expression in various classes of differentiating neurons. We provide evidence that these two UNC-5 homologues, as well as the rcm gene product, are netrin-binding proteins, supporting the hypothesis that UNC-5 and its relatives are netrin receptors.

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