title: UNC-129 regulates the balance between UNC-40 dependent and independent UNC-5 signaling pathways.
abstract: The UNC-5 receptor mediates axon repulsion from UNC-6/netrin through UNC-40 dependent (UNC-5 + UNC-40) and independent (UNC-5 alone) signaling pathways. It has been shown that UNC-40-dependent signaling is required for long-range repulsion of UNC-6/netrin; however, the mechanisms used to regulate distinct UNC-5 signaling pathways are poorly understood. We found that the C. elegans transforming growth factor beta (TGF-beta) family ligand UNC-129, graded opposite to UNC-6/netrin, functions independent of the canonical TGF-beta receptors to regulate UNC-5 cellular responses. Our observations indicates that UNC-129 facilitates long-range repulsive guidance of UNC-6 by enhancing UNC-5 + UNC-40 signaling at the expense of UNC-5 alone signaling through interaction with the UNC-5 receptor. This increases the set point sensitivity of growth cones to UNC-6/netrin as they simultaneously migrated up the UNC-129 gradient and down the UNC-6 gradient. Similar regulatory interactions between oppositely graded extracellular cues may be a common theme in guided cell and axon migrations.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Lesley T
authors.initials: LT
authors.lastname: MacNeil
authors.forename: W Rod
authors.initials: WR
authors.lastname: Hardy
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Culotti
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D019556:COS Cells; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D002522:Chlorocebus aethiops; D018507:Gene Expression Regulation, Developmental; D020439:Growth Cones / Q000502:physiology; D016296:Mutagenesis; D009420:Nervous System / Q000166:cytology / Q000196:embryology*; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; C113622:UNC-129 protein, C elegans; C102174:UNC-40 protein, C elegans; C077588:UNC-5 protein, C elegans