The polarity protein VANG-1 antagonizes Wnt signaling by facilitating Frizzled endocytosis
Abstract
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.
Additional Information
© 2018 Published by The Company of Biologists Ltd. Received 8 June 2018; Accepted 16 November 2018; Published 17 December 2018. We thank Gian Garriga and the C. elegans Genetics Center (CGC) for worm strains. CGC is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). The authors declare no competing or financial interests. Author contributions: Conceptualization: C.-W.H., C.-L.P.; Methodology: C.-W.H., C.-L.P.; Validation: C.-L.P.; Formal analysis: C.-W.H., C.-L.P.; Investigation: C.-W.H., C.-P.L., C.-K.C., J.T., C.-H.C., C.-L.P.; Data curation: C.-W.H., C.-P.L., C.-K.C., J.T., C.-L.P.; Writing - original draft: C.-W.H., C.-L.P.; Writing - review & editing: C.-W.H., C.-P.L., C.-K.C., J.T., C.-H.C., C.-L.P.; Visualization: C.-W.H., C.-L.P.; Supervision: C.-L.P.; Project administration: C.-L.P.; Funding acquisition: C.-L.P. This study was funded by the Ministry of Science and Technology, Taiwan (MOST 103-2320-B-002-050-MY3, MOST 106-2320-B-002-051-MY3 to C.-L.P.). Supplementary information: Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.168666.supplemental.Attached Files
Published - dev168666.full.pdf
Supplemental Material - DEV168666supp.pdf
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Additional details
- Eprint ID
- 92342
- Resolver ID
- CaltechAUTHORS:20190117-103941778
- P40 OD010440
- NIH
- MOST 103-2320-B-002-050-MY3
- Ministry of Science and Technology (Taipei)
- MOST 106-2320-B-002-051-MY3
- Ministry of Science and Technology (Taipei)
- Created
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2019-01-22Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field