Exploring Planar Cell Polarity in A Novel Invertebrate Chordate System

描述（由申请人提供）：组织和器官的正常功能需要极化细胞。细胞通过各种机制获得极化形态（即细胞一侧与另一侧亚细胞成分的差异），包括平面细胞极性（PCP）途径，这是本提案的主题。PCP途径的许多分子成分已经被表征，包括上游跨膜Fz受体和下游因子，disheveled，刺痛，斜视，火烈鸟等。PCP通路负责产生极化的细胞形态和行为，并在组织范围内协调极性。关于PCP通路的许多信息仍然知之甚少，包括PCP机制与细胞结构和功能成分极化的联系机制，以及组织和器官极性在全球水平上决定的机制。本应用提出以被囊动物脊索为模型研究PCP通路。被囊动物是现存脊椎动物的近亲，但它们的基因组要小得多，形态也更简单，尽管相似。这种简单可见于仅由40个细胞组成的中脑脊索。在中脑脊索中，pcp依赖机制首先负责细胞在中/侧轴的定向嵌入，形成一个柱。插入完成后，PCP通路发出脊索细胞第二次极化的信号，这次是在前/后轴。在第一个特定目标中提出的实验将通过检查核心PCP蛋白定位的时空变化来更全面地表征Ciona脊索极性，并将解决从中/侧极性到前/后极性的转变以及这两个极性如何相互联系。第二个具体目标将研究全局极性建立的机制以及细胞间信号传导在极性传播和维持中的作用。最后，第三个具体目标将试图揭示作用于中/外侧和前/后轴的全局极化信号的分子身份。

DESCRIPTION (provided by applicant): The proper functioning of tissues and organs requires polarized cells. Cells acquire polarized morphologies (i.e., differences in subcellular composition from one side of the cell to the other) through various mechanisms, including the planar cell polarity (PCP) pathway, which is the subject of this proposal. A number of molecular components of the PCP pathway have been characterized, including the upstream transmembrane Fz receptor and the downstream factors, disheveled, prickle, strabismus, flamingo, and others. The PCP pathway is responsible for generating polarized cell morphologies and behaviors, and for coordinating polarity on a tissue-wide scale. Much about the PCP pathway remains poorly understood, including the mechanisms that link PCP machinery to polarization of structural and functional components of the cell, and the mechanism by which the polarity of tissues and organs is determined at a global level. This application proposes to use the notochord of the tunicate Ciona as a model to study the PCP pathway. Tunicates are the closest extant relatives of vertebrates, but have much smaller genomes, and simpler, though similar, morphology. This simplicity is seen in the Ciona notochord which consists of only forty cells. In the Ciona notochord, PCP-dependant mechanisms are responsible, first, for the directed intercalation of cells in the medio/lateral axis to form a column. At the completion of intercalation, the PCP pathway signals a second polarization of the notochord cells, this time in the anterior/posterior axis. Experiments proposed in the first specific aim will more fully characterize Ciona notochord polarity by examining the temporal and spatial changes in core PCP protein localization, and will address the transition from medio/lateral to anterior/posterior polarity and how these two polarities are linked. The second specific aim will investigate mechanisms by which global polarity is established and the role of cell-to-cell signaling in propagation and maintenance of polarity. Finally, the third specific aim will attempt to uncover the molecular identity(ies) of the global polarizing signals acting both in the medio/lateral and anterior/posterior axes. PUBLIC HEALTH RELEVANCE: Defects in cell polarity are associated with many human disease conditions, such as polycystic kidney disease. The proposal will investigate the fundamental cellular mechanism that underlies the formation of cell polarities.