title: C. elegans PVF-1 inhibits permissive UNC-40 signalling through CED-10 GTPase to position the male ray 1 sensillum.
abstract: Graded distributions of netrin and semaphorin guidance cues convey instructive polarity information to migrating cells and growth cones, but also have permissive (i.e. non-polarity determining) functions in mammalian development and repair. The permissive functions of these cues are largely uncharacterised at a molecular level. We found previously that UNC-6 (netrin) signals permissively through UNC-40 (DCC) and UNC-5 receptors to prevent anterior displacement of the ray 1 sensillum in the C. elegans male tail. UNC-6/UNC-40 signalling functions in parallel with SMP-1 (semaporin 1)/PLX-1 (plexin) signalling to prevent this defect. Here, we report that a deletion allele of pvf-1, which encodes a VEGF-related protein, causes no ray 1 defects, but enhances ray 1 defects of a plx-1 mutant, and unexpectedly also suppresses unc-6(ev400)-null mutant ray 1 defects. These mutant ray 1 inductive and suppressive effects are mimicked by the ability of unc-40(+) and ced-10(gain-of-function) multi-copy transgene arrays to induce ray 1 defects or suppress unc-6 mutant ray 1 defects, depending on their dosage, suggesting the pvf-1 mutation causes UNC-40 overactivity that interferes with signalling but is partially sensitive to UNC-6. Additional data suggest PVF-1 functions through four VEGF receptor-related proteins and inhibits only CED-10 (a GTPase), but not MIG-2-dependent UNC-40 activity, even though UNC-40 functions through both GTPases to position ray 1. pvf-1 and receptor mutant ray 1 defects are rescued by transgenes expressing mouse VEGF164 and human VEGF receptors, respectively. These data report the first case of VEGF-induced inhibition of the netrin signalling and a molecular conservation of VEGF function from worms to humans.
authors.affiliation: Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
authors.forename: Gratien
authors.initials: G
authors.lastname: Dalpe
authors.forename: Marina
authors.initials: M
authors.lastname: Tarsitano
authors.forename: M Graziella
authors.initials: MG
authors.lastname: Persico
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Joseph
authors.initials: J
authors.lastname: Culotti
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D058618:Sensilla / Q000378:metabolism*; D013623:Tail / Q000254:growth & development / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C407268:CED-10 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; C508617:PVF-1 protein, C elegans; D010982:Platelet-Derived Growth Factor; C102174:UNC-40 protein, C elegans; D020744:rac GTP-Binding Proteins
keywords: Crosstalk; GTPase; PVF-1/VEGF; UNC-40/DCC