SIGNALING MECHANISMS CONTROLLING PLANAR CELL POLARITY

描述：（从申请人的描述逐字）：虽然很多工作有 解决了上皮细胞中顶-底极性的测定，相对 很少有人知道正交极性的规格 顶基轴[称为平面细胞极性（PCP）]。然而，尽管如此， PCP是许多组织系统功能的组成部分， 哺乳动物耳的特殊毛细胞到耳的动态纤毛 气管和生殖道上皮。平面极性可能不会 不仅对极化上皮结构的建立，而且对 细胞以定向方式进行交流的能力。很可能 定向信号机制在发育中具有普遍的重要性。 这项建议的目的是阐明，使用一个遗传上易于处理的 系统，信号定向上皮细胞骨架的机制 细胞沿着与其顶基轴正交的轴。一组功能强大的 基因、分子和表型工具使果蝇成为一种 有吸引力的系统调查控制PCP。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以下作用： 卷曲和凌乱，从而暗示Wnt作为配体。五氯苯酚知识 因此，信号传递也将有助于我们理解 Wnt/Frizzled信号传导机制和反应。 PCP信号需要建立亚细胞的不对称性， 细胞外信号我们之前的结果使我们测试了模型，在 在体内，亚细胞对PCP信号反应的不对称性是由 Dishevelled蛋白的不对称再定位。Disshevelled可以 作为建立内在极性的标志， 细胞骨架重组事实上，我们已经证明了 与此模型一致的Dishevelled分离。这项建议 描述了旨在描述Dishevelled角色的实验， 产生不对称PCP反应的其他蛋白质。具体而言是 该提案的目的是1）确定Dsh的不对称分离 在PCP响应期间有助于细胞极化，2）识别 信号通路的其他成分可能参与 转导PCP信号，和3）表征一些新发现的 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.