Abstract
Planar cell polarity (PCP) is an evolutionarily conserved essential mechanism that provides directional information to control and coordinate polarized cellular and tissue behavior during embryonic development. Disruption of PCP leads to severe morphological defects in vertebrates and its dysregulation results in a variety of human diseases such as neural tube defects and skeletal dysplasia. PCP is governed by a set of highly conserved core proteins that are asymmetrically localized at the cell surface throughout the polarized tissues. The uniform directionality of PCP is established by global cues, such as Wg/Wnt signaling gradients that break the original symmetrical localization of core PCP proteins including Vang/Vangl and Fz/Fzd. However, the exact mechanism remains elusive. In this study, we found that Vangl2 phosphorylation, which was previously identified to be induced by Wnt5a signaling, is required for Vangl2 functions in mammalian PCP in multiple tissues. The in vivo activities of Vangl2 are determined by its phosphorylation level. Phospho-mutant Vangl2 exhibits dominant negative effects, whereas Vangl2 with reduced phosphorylation is hypomorphic. We show that Vangl2 phosphorylation is essential for its uniform polarization pattern. Moreover, serine/threonine kinases CK1ɛ and CK1δ are redundantly required for Wnt5a-induced Vangl2 phosphorylation. Dvl family members are also required for Wnt5a-induced Vangl2 phosphorylation by enhancing the interaction of CK1 and Vangl2. These findings demonstrate that induction of Vangl protein phosphorylation plays an essential role in transducing Wnt5a signaling to establish PCP in mammalian development, suggesting a phosphorylation-regulated “Vangl activity gradient” model in addition to the well-documented “Fz activity gradient” model in Wnt/PCP signaling.
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Acknowledgements
We thank Jun Cheng, Cecilia Rivas, and Elsa Escobar for their assistance in generating transgenic mice, Guadalupe Lopez for mouse husbandry and Jing Guo for confocal microscopy. The Ror2 mutant mouse was provided by Yasuhiro Minami. The β-actin-Cre mouse was provided by Kathryn SE Cheah. The work in the Gao laboratory was supported by the University of Hong Kong Start-up funds and Hong Kong Research Grants Council (27115317). The work in the Yang laboratory was supported by the intramural research program of NHGRI at the US National Institutes of Health (NIH), NIH/NIAMS grant R01AR070877 and the Harvard School of Dental Medicine Start-up funds.
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Supplementary information
Supplementary information, Figure S1
Alignment of N-terminus of Vangl1 and Vangl2 protein sequences across multiple species. (PDF 746 kb)
Supplementary information, Figure S2
Vangl2 phosphorylation is required for its stable membrane localization. (PDF 1391 kb)
Supplementary information, Figure S3
Dominant negative effects of mutant Vangl2. (PDF 1557 kb)
Supplementary information, Figure S4
Stability of phospho-mutant Vangl2. (PDF 989 kb)
Supplementary information, Figure S5
The tissue axes used to define the Vangl2 localization pattern and measure the cell orientation. (PDF 588 kb)
Supplementary information, Figure S6
The localization of phospho-mutant Vangl2 puncta. (PDF 937 kb)
Supplementary information, Figure S7
Vangl2 phosphorylation is required for its uniform asymmetric localization pattern and polarized cellular behaviors in skin epidermal cells. (PDF 1615 kb)
Supplementary information, Figure S8
The cellular localization of Vangl2 with CK1 inhibition. (PDF 660 kb)
Supplementary information, Figure S9
Vangl23A/3A is sensitive to the dose of CK1 in a limb culture model. (PDF 1343 kb)
Supplementary information, Table S1
The number of embryos collected in different genotype. (PDF 385 kb)
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Yang, W., Garrett, L., Feng, D. et al. Wnt-induced Vangl2 phosphorylation is dose-dependently required for planar cell polarity in mammalian development. Cell Res 27, 1466–1484 (2017). https://doi.org/10.1038/cr.2017.127
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DOI: https://doi.org/10.1038/cr.2017.127
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