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间的接触或粘连而相互连接。这些粘连对于维持组织的完整性和细胞间的沟通是必不可少的。当细胞间的粘附力受损时，细胞可能会脱离邻近细胞而变得侵袭，或者依赖紧密接触进行信号传输的细胞，如神经细胞，可能会失去在相邻细胞之间传递信号的能力。这类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Dkk1的分子上，这是一种在胚胎发育过程中诱导头部形成的分泌蛋白。Dkk1经常在几种癌症中被检测到，这些癌症的水平升高与疾病进展和不良预后有关，也与神经细胞之间的信号丢失有关，称为突触信号，这与阿尔茨海默病有关。Dkk1在这些疾病中的功能作用尚未解决。利用斑马鱼胚胎作为体内模型，我们最近报道了Dkk1由于减少了细胞与细胞的黏附而扰乱了胚胎中细胞群的迁移，并且这是通过一种不同于其已知信号功能的机制发生的。我们现在提议进行实验，以深入了解DKK1是如何通过在体内寻找相互作用伙伴来降低细胞与细胞之间的黏附，并研究它们如何在调节细胞黏附和细胞行为中对DKK1的S功能做出贡献。我们还发现了一个与协调细胞分裂的结构相关的Dkk1池，我们也建议对其进行进一步研究。深入了解DKK1影响细胞行为和细胞分裂的机制，对于理解DKK1在癌症和神经退行性疾病中的S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.