title: UNC-6/netrin and its receptors UNC-5 and UNC-40/DCC modulate growth cone protrusion in vivo in C. elegans.
abstract: The UNC-6/netrin guidance cue functions in axon guidance in vertebrates and invertebrates, mediating attraction via UNC-40/DCC family receptors and repulsion via by UNC-5 family receptors. The growth cone reads guidance cues and extends lamellipodia and filopodia, actin-based structures that sense the extracellular environment and power the forward motion of the growth cone. We show that UNC-6/netrin, UNC-5 and UNC-40/DCC modulated the extent of growth cone protrusion that correlated with attraction versus repulsion. Loss-of-function unc-5 mutants displayed increased protrusion in repelled growth cones, whereas loss-of-function unc-6 or unc-40 mutants caused decreased protrusion. In contrast to previous studies, our work suggests that the severe guidance defects in unc-5 mutants may be due to latent UNC-40 attractive signaling that steers the growth cone back towards the ventral source of UNC-6. UNC-6/Netrin signaling also controlled polarity of growth cone protrusion and F-actin accumulation that correlated with attraction versus repulsion. However, filopodial dynamics were affected independently of polarity of protrusion, indicating that the extent versus polarity of protrusion are at least in part separate mechanisms. In summary, we show here that growth cone guidance in response to UNC-6/netrin involves a combination of polarized growth cone protrusion as well as a balance between stimulation and inhibition of growth cone (e.g. filopodial) protrusion.
authors: Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA.
authors: Adam D
authors: AD
authors: Norris
authors: Erik A
authors: EA
authors: Lundquist
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning; 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*; D002465:Cell Movement; D016764:Cell Polarity; D017238:Genes, Helminth; D020439:Growth Cones / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000075385:Netrins; D055495:Neurogenesis; D010641:Phenotype; D011554:Pseudopodia / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059008:Time-Lapse Imaging
chemical_list: D000199:Actins; D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; D009419:Nerve Tissue Proteins; D000075385:Netrins; D011956:Receptors, Cell Surface; C102174:UNC-40 protein, C elegans; C078146:UNC-6 protein, C elegans; C077588:UNC-5 protein, C elegans