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

细胞通过在相邻细胞之间形成细胞-细胞接触或粘附而彼此连接。这些粘附对于维持组织完整性和细胞之间的通讯是必不可少的。当细胞间粘附受到损害时，细胞可能会从它们的邻居中挣脱出来并变得具有侵袭性，或者依赖于紧密接触进行信号传输的细胞（如神经细胞）可能会失去它们在相邻细胞之间传递信号的能力。这些事件的后果往往与人类疾病有关。我们的研究集中在一种名为Dkk 1的分子上，这是一种分泌蛋白，在胚胎发育过程中诱导头部形成。Dkk 1经常在几种癌症中检测到，其水平升高与疾病进展和预后不良相关，并且还与神经细胞之间的信号传导（称为突触信号传导）的丢失相关，这与阿尔茨海默病有关。Dkk 1在这些疾病中的功能作用尚未解决。使用斑马鱼胚胎作为体内模型，我们最近报道了Dkk 1由于细胞间粘附减少而破坏胚胎中细胞群的迁移，并且这是通过不同于其已知信号功能的机制发生的。我们现在建议进行实验，以深入了解Dkk 1如何通过识别体内相互作用伙伴来降低细胞间粘附，并研究它们如何有助于Dkk 1在调节细胞粘附和细胞行为中的功能。我们还发现了一个与协调细胞分裂的结构相关的Dkk 1库，我们建议进一步研究。深入了解Dkk 1影响细胞行为和细胞分裂的机制对于理解Dkk 1在癌症和神经退行性疾病中的作用至关重要。

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.