The netrin receptor UNC-40/DCC stimulates axon attraction and outgrowth through enabled and, in parallel, Rac and UNC-115/AbLIM.
Netrins promote axon outgrowth and turning through DCC/UNC-40 receptors. To characterize Netrin signaling, we generated a gain-of-function UNC-40 molecule, MYR::UNC-40. MYR::UNC-40 causes axon guidance defects, excess axon branching, and excessive axon and cell body outgrowth. These defects are suppressed by loss-of-function mutations in ced-10 (a Rac GTPase), unc-34 (an Enabled homolog), and unc-115 (a putative actin binding protein). ced-10, unc-34, and unc-115 also function in endogenous unc-40 signaling. Our results indicate that Enabled functions in axonal attraction as well as axon repulsion. UNC-40 has two conserved cytoplasmic motifs that mediate distinct downstream pathways: CED-10, UNC-115, and the UNC-40 P2 motif act in one pathway, and UNC-34 and the UNC-40 P1 motif act in the other. Thus, UNC-40 might act as a scaffold to deliver several independent signals to the actin cytoskeleton.
Gitai
Zemer
Z
Howard Hughes Medical Institute, Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Yu
Timothy W
TW
Lundquist
Erik A
EA
Tessier-Lavigne
Marc
M
Bargmann
Cornelia I
CI
D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016153:Genes, Suppressor / Q000502:physiology; D020439:Growth Cones / Q000378:metabolism* / Q000648:ultrastructure; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009420:Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D009421:Nervous System Malformations / Q000235:genetics / Q000473:pathology; D000075386:Netrin Receptors; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000235:genetics*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
C407268:CED-10 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C092744:ENA-VASP proteins; D008840:Microfilament Proteins; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C472306:UNC-115 protein, C elegans; C102174:UNC-40 protein, C elegans; D020744:rac GTP-Binding Proteins