title: Vangl2 promotes Wnt/planar cell polarity-like signaling by antagonizing Dvl1-mediated feedback inhibition in growth cone guidance.
abstract: Although a growing body of evidence supports that Wnt-Frizzled signaling controls axon guidance from vertebrates to worms, whether and how this is mediated by planar cell polarity (PCP) signaling remain elusive. We show here that the core PCP components are required for Wnt5a-stimulated outgrowth and anterior-posterior guidance of commissural axons. Dishevelled1 can inhibit PCP signaling by increasing hyperphosphorylation of Frizzled3 and preventing its internalization. Vangl2 antagonizes that by reducing Frizzled3 phosphorylation and promotes its internalization. In commissural axon growth cones, Vangl2 is predominantly localized on the plasma membrane and is highly enriched on the tips of the filopodia as well as in patches of membrane where new filopodia emerge. Taken together, we propose that the antagonistic functions of Vangl2 and Dvl1 (over Frizzled3 hyperphosphorylation and endocytosis) allow sharpening of PCP signaling locally on the tips of the filopodia to sense directional cues, Wnts, eventually causing turning of growth cones.
authors.affiliation: Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Shafer
authors.forename: Keisuke
authors.initials: K
authors.lastname: Onishi
authors.forename: Charles
authors.initials: C
authors.lastname: Lo
authors.forename: Gulsen
authors.initials: G
authors.lastname: Colakoglu
authors.forename: Yimin
authors.initials: Y
authors.lastname: Zou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D019521:Body Patterning; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity; D000072261:Dishevelled Proteins; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation; D025461:Feedback, Physiological; D051157:Frizzled Receptors / Q000378:metabolism; D020439:Growth Cones / Q000201:enzymology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; C000606580:Dvl1 protein, rat; D051157:Frizzled Receptors; C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases