The polarity protein VANG-1 antagonizes Wnt signaling by facilitating Frizzled endocytosis [RESEARCH ARTICLE]

Chun-Wei He, Chien-Po Liao, Chung-Kuan Chen, Jerome Teuliere, Chun-Hao Chen, and Chun-Liang Pan

Signaling that instructs the migration of neurons needs to be tightly regulated to ensure precise positioning of neurons and subsequent wiring of the neuronal circuits. Wnt-Frizzled signaling controls neuronal migration in metazoans, in addition to many other aspects of neural development. We show that Caenorhabditis elegans VANG-1, a membrane protein that acts in the planar cell polarity (PCP) pathway, antagonizes Wnt signaling by facilitating endocytosis of the Frizzled receptors. Mutations of vang-1 suppress migration defects of multiple classes of neurons in the Frizzled mutants, and overexpression of vang-1 causes neuronal migration defects similar to those of the Frizzled mutants. Our genetic experiments suggest that VANG-1 facilitates Frizzled endocytosis through β-arrestin2. Co-immunoprecipitation experiments indicate that Frizzled proteins and VANG-1 form a complex, and this physical interaction requires the Frizzled cysteine-rich domain. Our work reveals a novel mechanism mediated by the PCP protein VANG-1 that downregulates Wnt signaling through Frizzled endocytosis.

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