SIGNALING MECHANISMS CONTROLLING PLANAR CELL POLARITY

描述：(逐字摘自申请者的描述)：鉴于有很多工作 阐述了上皮细胞根尖-基底极性的测定，相对地 关于正交极性的规范，我们知之甚少 尖-基轴[称为平面细胞极性(PCP)]。不过， PCP是许多组织系统功能不可或缺的一部分，从 哺乳动物耳部的特化毛细胞与耳缘的动态纤毛 气管和生殖道上皮。平面极性可能不起作用 不仅对极化上皮结构的建立，而且对 细胞以定向方式通信的能力。很可能是 定向信号机制在发育中具有无处不在的重要性。 这项提议的目标是阐明，使用一种遗传上容易驯服的 系统，信号定位上皮细胞骨架的机制(S) 细胞沿与其顶端-基生轴垂直的轴排列。一套强大的 遗传、分子和表型工具使果蝇成为 具有吸引力的系统，用于研究五氯酚的控制措施。我们将使用 果蝇作为我们的主要模型系统。 对调节PCP的信号通路的剖析揭示了 卷曲和凌乱，从而牵连WNT作为配体。关于PCP的知识 因此，信号也将有助于我们对多样性的理解 WNT/FrizzledSignal机制和响应。 PCP信号需要建立亚细胞不对称性来响应 到细胞外的暗示。我们之前的结果使我们测试了该模型，在 在体内，响应PCP信号的亚细胞不对称是由 蓬乱的蛋白质的不对称重定位。蓬头垢面的人就可以 作为建立固有极性的标记，并引导由此产生的 细胞骨架重组。事实上，我们已经证明了不对称 蓬头垢面的隔离符合这一模式。这项建议 描述了旨在描述蓬头垢面的角色和 产生不对称PCP反应的其他蛋白质。具体地说， 该建议的目的是：1)确定Dsh的非对称分离 在PCP响应过程中有助于细胞极化，2)识别 可能参与的信号通路的其他组成部分 转换PCP信号，以及3)表征其中一些新发现的 组件。

DESCRIPTION: (Verbatim from the applicant's description): Whereas much work has addressed the determination of apical-basal polarity in epithelia, relatively little is known about the specification of polarity orthogonal to the apical-basal axis [referred to as planar cell polarity (PCP)]. Nevertheless, PCP is integral to the function of many tissue-systems ranging from the specialized hair cells of the mammalian ear to the dynamic cilia of the tracheal and reproductive tract epithelia. Planar polarity might contribute not only to the establishment of polarized epithelial structures, but also to the ability of cells to communicate in a directional fashion. It is likely that directional signaling mechanisms are of ubiquitous importance in development. The goal of this proposal is to elucidate, using a genetically tractable system, the mechanism(s) by which signals orient the cytoskeleton of epithelial cells along an axis orthogonal to their apical-basal axes. A powerful set of genetic, molecular and phenotypic tools makes Drosophila an extremely attractive system for investigating the controls governing PCP. We will use Drosophila as our primary model system. Dissection of the signaling pathway regulating PCP has revealed roles for Frizzled and Dishevelled, thereby implicating a Wnt as ligand. Knowledge of PCP signaling will therefore also contribute to our understanding of the diversity of Wnt/Frizzled signaling mechanisms and responses. PCP signaling requires the establishment of subcellular asymmetry in response to extracellular cues. Our previous results led us to test the model that, in vivo, subcellular asymmetry in response to the PCP signal results from an asymmetric relocalization of the Dishevelled protein. Dishevelled could then serve as a marker establishing intrinsic polarity and directing the resulting cytoskeletal reorganization. Indeed, we have demonstrated asymmetric segregation of Dishevelled that is consistent with this model. This proposal describes experiments aimed at characterizing the roles of Dishevelled and other proteins in generation of an asymmetric PCP response. Specifically, the aims of this proposal are to 1) determine how asymmetric segregation of Dsh contributes to cell polarization during the PCP response, 2) identify additional components of the signaling pathway that may be involved in transducing the PCP signal, and 3) characterize some of these newly identified components.