Vangl2 Promotes Wnt/Planar Cell Polarity-like Signaling by Antagonizing Dvl1-Mediated Feedback Inhibition in Growth Cone Guidance

• Published in: Developmental cell Vol. 20; no. 2; pp. 177 - 191
• Main Authors: Shafer, Beth, Onishi, Keisuke, Lo, Charles, Colakoglu, Gulsen, Zou, Yimin
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 15.02.2011; Cell Press
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Biological and medical sciences; Body Patterning; Cell differentiation, maturation, development, hematopoiesis; Cell Membrane - metabolism; Cell physiology; Cell Polarity; Dishevelled Proteins; Embryo, Mammalian - metabolism; Enzyme Activation; Feedback, Physiological; Frizzled Receptors - metabolism; Fundamental and applied biological sciences. Psychology; Growth Cones - enzymology; Growth Cones - metabolism; HEK293 Cells; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Mice; Molecular and cellular biology; Nerve Tissue Proteins - metabolism; Phosphoproteins - metabolism; Phosphorylation; Protein Transport; Pseudopodia - metabolism; Rats; Signal Transduction; Wnt Proteins - metabolism; Wnt-5a Protein; Cone; Feedback; Growth; Cellular polarity; Development; Inhibition; Cell signaling
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2011.01.002

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. [Display omitted] ► Planar cell polarity components mediate A-P guidance of commissural axons by Wnts ► Dvl1 suppresses PCP signaling by inducing p-Fzd3 and blocking its internalization ► Vangl2 antagonizes Dvl1 by reducing p-Fzd3 and promoting its internalization ► Vangl2 is enriched on growing filopodia tips where guidance cues may be detected