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

SummaryAlthough 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (95 K)Download as PowerPoint slideHighlights► 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