title: The UNC-6/Netrin receptors UNC-40/DCC and UNC-5 inhibit growth cone filopodial protrusion via UNC-73/Trio, Rac-like GTPases and UNC-33/CRMP.
abstract: UNC-6/Netrin is a conserved axon guidance cue that can mediate both attraction and repulsion. We previously discovered that attractive UNC-40/DCC receptor signaling stimulates growth cone filopodial protrusion and that repulsive UNC-40-UNC-5 heterodimers inhibit filopodial protrusion in C. elegans. Here, we identify cytoplasmic signaling molecules required for UNC-6-mediated inhibition of filopodial protrusion involved in axon repulsion. We show that the Rac-like GTPases CED-10 and MIG-2, the Rac GTP exchange factor UNC-73/Trio, UNC-44/Ankyrin and UNC-33/CRMP act in inhibitory UNC-6 signaling. These molecules were required for the normal limitation of filopodial protrusion in developing growth cones and for inhibition of growth cone filopodial protrusion caused by activated MYR::UNC-40 and MYR::UNC-5 receptor signaling. Epistasis studies using activated CED-10 and MIG-2 indicated that UNC-44 and UNC-33 act downstream of the Rac-like GTPases in filopodial inhibition. UNC-73, UNC-33 and UNC-44 did not affect the accumulation of full-length UNC-5::GFP and UNC-40::GFP in growth cones, consistent with a model in which UNC-73, UNC-33 and UNC-44 influence cytoskeletal function during growth cone filopodial inhibition.
authors.affiliation: Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, The University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Norris
authors.affiliation: Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, The University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Sundararajan
authors.affiliation: Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, The University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA.
authors.forename: Dyan E
authors.initials: DE
authors.lastname: Morgan
authors.affiliation: Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, The University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Roberts
authors.affiliation: Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, The University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA erikl@ku.edu.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Lundquist
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004843:Epistasis, Genetic / Q000502:physiology; D020439:Growth Cones / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000075385:Netrins; D011554:Pseudopodia / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D059008:Time-Lapse Imaging; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075385:Netrins; D011956:Receptors, Cell Surface; C102174:UNC-40 protein, C elegans; C078146:UNC-6 protein, C elegans; C111263:UNC-73 protein, C elegans; C078652:unc-33 protein, C elegans; C077588:UNC-5 protein, C elegans; C442327:Mig-2 protein, C elegans; D020744:rac GTP-Binding Proteins
keywords: Axon repulsion; Caenorhabditis elegans; Filopodia; Growth cone; UNC-40/DCC; UNC-5; UNC-6