In a landmark paper, just published, Johansson et al. describe the mechanism by which Dickkopf-1 profoundly modifies cellular characteristics which could begin to explain why the protein has been implicated in cancer metastasis and neurodegenerative disease.
Dickkopf-1 (Dkk1) is a secreted Wnt antagonist with a known role in cell fate determination and head induction during embryonic development. The protein is also expressed during adulthood and has a role in tissue regeneration and repair. Deregulated expression has been associated with the metastasis of several cancers and overexpression has been found in post-mortem brain tissue of people with Alzheimer’s disease. However, how Dkk1 acts in these diseases has remained unknown.
CDN colleagues in the Houart lab - Marie Johansson, Florence Giger, Triona Fielding and Corinne Houart – for the first time unveil a novel mechanism for Dkk1 in their paper in Developmental Cell. Marie and colleagues used zebrafish gastrulation as a model, a dynamic process where cells at the margin of the developing embryo internalise and migrate to form the mesoderm germ layer. Crucially, during this migration, cells within a group remain connected whilst moving.
From their experiments, the authors found that Dkk1 controls cell polarity and how groups of cells move and connect with each other, by a mechanism independent of Dkk1’s previously known roles. Dkk1 localises to adhesion complexes at the plasma membrane and regions of concentrated actomyosin – findings that suggest the protein has a direct involvement in regulating local cell adhesion. Dkk1 represses cell polarisation and the integrity of cell-cell adhesion independently of its impact on β-catenin protein degradation.
These novel actions of Dkk1 are potentially very significant for understanding the protein’s role in disease. Marie and colleagues consider that Dkk1 may contribute to synaptic loss in neurodegenerative disease through downregulating synaptic adhesion. Further investigations into Dkk1’s role in synaptic adhesion could help to unravel the mystery of neurodegeneration as well as understand how the protein acts in cancer metastasis.