Developmental Cell
Volume 51, Issue 6, 16 December 2019, Pages 775-786.e3
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Article
Dkk1 Controls Cell-Cell Interaction through Regulation of Non-nuclear β-Catenin Pools

https://doi.org/10.1016/j.devcel.2019.10.026Get rights and content
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Highlights

  • Dkk1 localizes to adhesion complexes in vivo

  • Dkk1 signaling controls cell-cell connectivity and polarity

  • Cell interaction control is independent of β-catenin transcriptional output and Wnt/PCP

  • Dkk1 sequesters β-catenin at the plasma membrane

Summary

Dickkopf-1 (Dkk1) is a secreted Wnt antagonist with a well-established role in head induction during development. Numerous studies have emerged implicating Dkk1 in various malignancies and neurodegenerative diseases through an unknown mechanism. Using zebrafish gastrulation as a model for collective cell migration, we unveil such a mechanism, identifying a role for Dkk1 in control of cell connectivity and polarity in vivo, independent of its known function. We find that Dkk1 localizes to adhesion complexes at the plasma membrane and regions of concentrated actomyosin, suggesting a direct involvement in regulation of local cell adhesion. Our results show that Dkk1 represses cell polarization and integrity of cell-cell adhesion, independently of its impact on β-catenin protein degradation. Concurrently, Dkk1 prevents nuclear localization of β-catenin by restricting its distribution to a discrete submembrane pool. We propose that redistribution of cytosolic β-catenin by Dkk1 concomitantly drives repression of cell adhesion and inhibits β-catenin-dependent transcriptional output.

Keywords

Dickkopf-1
Dkk1
cell migration
cell adhesion
polarity
β-catenin
Wnt signaling morphogenesis
metastasis
neurodegeneration

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