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（即从细胞一侧到另一侧的亚细胞组成差异），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得到表征，包括上游跨膜 Fz 受体和下游因子、蓬乱、刺痛、斜视、火烈鸟等。 PCP 途径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 途径的许多内容仍然知之甚少，包括将 PCP 机制与细胞结构和功能成分的极化联系起来的机制，以及在全球水平上确定组织和器官极性的机制。本申请提出使用被囊动物 Ciona 的脊索作为模型来研究 PCP 途径。被囊动物是现存脊椎动物最接近的近亲，但其基因组要小得多，形态也更简单，尽管相似。这种简单性在海鞘脊索中可见一斑，它仅由四十个细胞组成。在玻璃海鞘脊索中，PCP 依赖性机制首先负责细胞在中/横轴上的定向嵌入以形成柱。嵌入完成后，PCP 通路发出脊索细胞第二次极化的信号，这次是在前/后轴。第一个具体目标中提出的实验将通过检查核心 PCP 蛋白定位的时间和空间变化来更全面地表征海鞘脊索极性，并将解决从中/侧极性到前/后极性的转变以及这两种极性如何联系。第二个具体目标将研究建立全局极性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，第三个具体目标将尝试揭示作用于中/横向和前/后轴的全局偏振信号的分子特性。 公共卫生相关性：细胞极性缺陷与许多人类疾病有关，例如多囊肾病。该提案将研究细胞极性形成的基本细胞机制。

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.