title: Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors.
abstract: 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 axons. 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 sources. 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 defects and ectopic expression of unc-5 in some neurons can redirect their axons away from a netrin source. 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), 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Anatomy, Programs in Cell and Developmental Biology and Neuroscience, University of California, San Francisco 94143-0452, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Leonardo
authors.forename: L
authors.initials: L
authors.lastname: Hinck
authors.forename: M
authors.initials: M
authors.lastname: Masu
authors.forename: K
authors.initials: K
authors.lastname: Keino-Masu
authors.forename: S L
authors.initials: SL
authors.lastname: Ackerman
authors.forename: M
authors.initials: M
authors.lastname: Tessier-Lavigne
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000502:physiology; D017173:Caenorhabditis elegans / Q000737:chemistry*; D029742:Caenorhabditis elegans Proteins; D002465:Cell Movement / Q000502:physiology; D015870:Gene Expression; D015801:Helminth Proteins / Q000737:chemistry*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000378:metabolism; D000075386:Netrin Receptors; D000075388:Netrin-1; D009474:Neurons / Q000166:cytology; D011487:Protein Conformation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000737:chemistry*; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D013116:Spinal Cord / Q000196:embryology / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins
chemical_list: D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D025521:Tumor Suppressor Proteins; C105653:Unc5c protein, mouse; C077588:UNC-5 protein, C elegans; D000075388:Netrin-1