Integration of cell-cell interactions and cell division by novel Dkk1 functions

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Cells connect to each other by forming cell-cell contacts, or adhesions, between neighbouring cells. These adhesions are essential for maintaining tissue integrity and for communication between cells. When intercellular adhesion is compromised, cells may break free from their neighbours and become invasive, or cells relying on close contact for signal transmission, such as nerve cells, may lose their ability to signal between neighbouring cells. The consequence of such events is often associated with human disease. Our research is centered on a molecule called Dkk1, a secreted protein that induces head formation during embryonic development. Dkk1 is frequently detected in several cancers with elevated levels correlating with disease progression and a poor prognosis, and is also associated with loss of signalling between nerve cells, called synaptic signalling, which is linked to Alzheimer's disease. The functional role of Dkk1 in these diseases is unresolved. Using the zebrafish embryo as an in vivo model, we have recently reported that Dkk1 disrupts migration of groups of cells in the embryo due to reduced cell-cell adhesion, and that this occurs by a mechanism different from its known signalling function. We now propose to carry out experiments to gain insight into how Dkk1 reduces cell-cell adhesion by identifying interaction partners in vivo and study how they contribute to Dkk1's function in regulation of cell adhesion and cell behaviour. We have also found a pool of Dkk1 associated with structures that orchestrate cell division, which we propose to also further investigate. Insight into the mechanisms by which Dkk1 impacts cell behaviour and cell division will be crucial for understanding Dkk1's role in cancer and neurodegenerative disease.