PCP-regulated directed cell motility

描述(申请人提供)：上皮细胞的功能通常需要在两个轴上极化，普遍存在的尖端-基底极性和上皮平面内的第二个轴，称为平面细胞极性(PCP)。典型的哺乳动物PCP的例子突出表现为皮肤和许多内脏的组织，例如内耳及其感觉纤毛，重要的是，还包括哺乳动物原肠形成和神经管关闭期间的定向细胞迁移。在果蝇中，所有的成体角质结构都显示出PCP特征。PCP在果蝇体内的建立为研究PCP在发育和疾病中的决定提供了一个范例。PCP是通过FrizzledFZ受体(以Wnt家族成员为配体)及其相关的信号级联(FZ/PCP信号)的活性来协调的，在整个进化过程中高度保守，并调节协调细胞极化的许多方面，包括定向细胞迁移。虽然调控PCP的信号通路(S)的框架已经开始建立，但PCP信号和由此产生的细胞反应之间的具体联系才刚刚开始剖析，包括细胞黏附和细胞运动的调节。同样，PCP途径的细胞黏附效应因子(S)在很大程度上是未知的。本应用的范围是以果蝇的眼睛为模型，剖析PCP相关的信号通路和相应的细胞黏附因子之间的机械调控相互作用。根据我们的初步研究，我们假设FZ/PCP、Notch和受体酪氨酸激酶(RTK)/RAS信号的调节信号集中在E-钙粘蛋白/连环蛋白、Nextin/Afadin和整合素/ECM介导的细胞黏附/细胞运动调节上。值得注意的是，所有涉及的信号通路(Wnt/Fz-PCP、Notch和RTK/RAS信号)都使用一个非规范的通路分支。这些细胞黏附特异性信号分支的组成部分现在才被发现，因此一个令人兴奋的新信号网络正在出现。我们将结合果蝇的活体研究、苍蝇眼的活体成像和生物化学实验来确定信号组件和细胞黏附因子之间的机械调控相互作用，从而导致高度调控的细胞运动过程。信号通路和细胞黏附模块的几个组成部分与癌症和其他疾病密切相关，也与干细胞生物学有关。因此，在这一应用中获得的信息不仅将促进我们对受调控的细胞运动性的理解，而且在几种疾病相关的情况下也将具有医学意义。

DESCRIPTION (provided by applicant): Epithelial cells often require polarization in two axes for their function, ubiquitous apical-basal polarity and a second axis within the plane of the epithelium, called Planar Cell Polarity (PCP). Typical mammalian PCP examples are highlighted by the organization of the skin and many internal organs, e.g. the inner ear with its sensory cilia and, importantly, also include directed cell migration during mammalian gastrulation and neural tube closure. In Drosophila, all adult cuticular structures show PCP features. The establishment of PCP in Drosophila serves as a paradigm to study PCP determination in development and disease. PCP is coordinated by the activity of the Frizzled (Fz) receptor (with Wnt family members as their ligands) and it's associated signaling cascade (Fz/PCP signaling), which is highly conserved throughout evolution and regulates many aspects of coordinated cellular polarization, including directed cell migration. Although the frame work of the signaling pathway(s) regulating PCP is beginning to be established, the specific links between PCP-signaling and the resulting cellular responses, including the regulation of cell adhesion and cell motility are only beginning to be dissected. Similarly, the cell adhesion effectors of the PCP pathway(s) are largely unknown. The scope of this application is to dissect the mechanistic regulatory interactions between PCP associated signaling pathways and the respective cell adhesion factors, using the Drosophila eye paradigm as a model. Based on our preliminary studies we hypothesize that regulatory input from Fz/PCP, Notch and receptor tyrosine kinase (RTK)/Ras signaling converges on E-cadherin/catenin, Nectin/Afadin, and Integrin/ECM mediated cell adhesion/cell motility regulation. Strikingly, all signaling pathways involved (Wnt/Fz-PCP, Notch and RTK/Ras-signaling) employ a non-canonical pathway branch. The components of these cell adhesion specific signaling branches are only being discovered now, and thus an exciting new signaling network is emerging. We will use a combination of Drosophila in vivo studies, live imaging in the fly eye, and biochemical experiments to define the mechanistic regulatory interactions between the signaling components and the cell adhesion factors, leading to a highly regulated cell motility process. Several components of the signaling pathways and cell adhesion modules are critically linked to cancer and other diseases, and are also associated with stem cell biology. Thus the information acquired in this application will not only advance our understanding of regulated cellular motility but will also be of medical relevance in several disease associated contexts.