PCP-regulated directed cell motility

描述（由申请人提供）：上皮细胞通常需要在两个轴上极化才能发挥其功能，普遍存在的顶基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的例子是皮肤和许多内部器官的组织，例如具有感觉纤毛的内耳，重要的是，还包括哺乳动物原肠胚形成和神经管闭合期间的定向细胞迁移。在果蝇中，所有成年的表皮结构都表现出PCP特征。果蝇PCP的建立为研究PCP在发育和疾病中的测定提供了一个范例。PCP是由frizzed （Fz）受体（Wnt家族成员作为其配体）的活性及其相关的信号级联（Fz/PCP信号）协调的，该信号级联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。尽管调控PCP的信号通路框架已经开始建立，但PCP信号传导与由此产生的细胞反应（包括细胞粘附和细胞运动的调节）之间的具体联系才刚刚开始被剖析。同样，PCP途径的细胞粘附效应物在很大程度上是未知的。本应用的范围是剖析PCP相关信号通路和各自细胞粘附因子之间的机制调节相互作用，使用果蝇眼范式作为模型。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信号的调节输入汇聚在E-cadherin/catenin， Nectin/Afadin和Integrin/ECM介导的细胞粘附/细胞运动调节上。引人注目的是，所有涉及的信号通路（Wnt/Fz-PCP， Notch和RTK/Ras-signaling）都采用非规范通路分支。这些细胞粘附特异性信号分支的成分现在才被发现，因此一个令人兴奋的新信号网络正在出现。我们将结合果蝇体内研究、蝇眼活体成像和生化实验来确定信号成分和细胞粘附因子之间的机制调节相互作用，从而导致高度调节的细胞运动过程。信号通路和细胞粘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，在此应用中获得的信息不仅将促进我们对受调节的细胞运动的理解，而且还将在几种疾病相关背景下具有医学相关性。

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.