Establishment of Epithelial Planar Cell Polarity

描述（由申请方提供）：上皮细胞需要正确的极性才能发挥功能。它们的极性和模式是在器官发生过程中建立的。上皮细胞通常在两个轴上极化，即在顶-基底外侧轴上和在上皮平面上，称为平面细胞极化或PCP。五氯苯酚的典型例子包括哺乳动物皮肤或内脏器官的特征，例如带有感觉纤毛的内耳上皮，以及无脊椎动物的昆虫表皮结构。在果蝇中PCP的建立可以作为研究PCP测定和极化细胞形状变化协调的范例。PCP由长程信号协调，导致Frizzled（Fz）受体及其相关信号级联（Fz/PCP信号）的激活。Fz/PCP途径在整个进化过程中是保守的，并且还调节协调的免疫系统的其他几个方面。 细胞极化，包括哺乳动物原肠胚形成期间的定向细胞迁移。值得注意的是，Fz/PCP 信号传导不同于典型的Wnt/Fz-B-连环蛋白途径。由相同受体激活的这两种途径之间的信号特异性调节仅知之甚少，但对发育和疾病至关重要。此外，Fz/PCP信号转导和所产生的细胞反应，包括细胞骨架重组和特定的转录事件之间的联系还不清楚。本申请的范围是调查新发现的基因的具体作用所需的PCP的测定和细胞形状变化的协调。它们在Fz/PCP信号和/或细胞极化事件中的功能将在遗传学和生物化学上进行研究。将利用果蝇体内研究、细胞培养分析和生化实验的组合来实现这些目标。PCP建立和Wnt/Fz信号传导的过程与几种医学异常（包括内耳上皮的耳聋）和癌症（该途径的几种组分是原癌基因或肿瘤抑制因子）有关。因此，在本申请中获得的信息将促进我们对细胞极化和模式化的理解，并且将具有医学相关性，特别是对于致癌作用的研究。

DESCRIPTION (provided by applicant): Epithelial cells require correct polarity for their function. Their polarity and patterning is established during organogenesis. Epithelial cells are often polarized in two axes, in the apical-basolateral axis and in the plane of the epithelium, called planar cell polarization or PCP. Typical PCP examples include features of mammalian skin or internal organs, e.g. the inner ear epithelium with its sensory cilia, and insect cuticular structures in invertebrates. The establishment of PCP in Drosophila serves as a paradigm to study PCP determination and the coordination of polarized cell shape changes in general. PCP is coordinated by long range signals, resulting in the activation of the Frizzled (Fz) receptor- and its associated signaling cascade (Fz/PCP signaling). The Fz/PCP pathway is conserved throughout evolution and also regulates several other aspects of coordinated cellular polarization, including directed cell migration during mammalian gastrulation. Strikingly, Fz/PCP signaling is distinct from the canonical Wnt/Fz-B-Catenin pathway. The regulation of signaling specificity between these two pathways activated by the same receptors is only poorly understood, but critical for development and disease. Moreover, the link between Fz/PCP signaling and the resulting cellular responses, including cytoskeletal reorganization and specific transcriptional events are not yet understood. The scope of this application is to investigate the specific roles of newly identified genes required for PCP determination and cell shape change coordination. Their function in Fz/PCP signaling and/or in cellular polarization events will be investigated genetically and biochemically. A combination of in vivo studies in Drosophila, cell culture analyses and biochemical experiments will be utilized to achieve these goals. The processes of PCP establishment and Wnt/Fz signaling have been linked to several medical abnormalities (including deafness in the case of the inner ear epithelium) and cancer (several components of the pathway are proto-oncogenes or tumor suppressors). Thus the information acquired in this application will both advance our understanding of cellular polarization and patterning, and will be of medical relevance, particularly for the study of carcinogenesis.