Cadherin regulation of tissue polarity and growth

描述（由申请人提供）：上皮平面细胞极性（PCP）是指组织细胞沿上皮平面内的均匀轴全部极化。在许多脊椎动物组织中都发现了PCP的重要生理例子，包括呼吸系统，其中纤毛细胞必须在一个统一的方向上极化，以便它们的跳动将粘液从肺部排出，以及耳朵，其中感觉毛细胞必须在一个统一的方向上极化，以便它们的立体纤毛正确排列以响应声音。关于PCP最重要的问题之一是单个细胞如何感知极化的正确方向。先前对果蝇的研究已经提供了这个问题的部分答案，表明细胞对Frizzled有反应，这是一种跨膜受体蛋白，其活性在整个组织中呈梯度存在。然而，Frizzled本身并不以分级方式表达，用于建立Frizzled信号梯度的机制也知之甚少。在最近的一项关于果蝇眼睛PCP的研究中，我们证明了脂肪，一种原钙粘蛋白，对于建立指导PCP的卷曲活性梯度是必不可少的。我们还发现脂肪在这一过程中受到Dachsous（另一种原钙粘蛋白）和Four-jointed（一种跨膜蛋白）的调节。我们进一步提出，Fat， Dachsous和Four-jointed可能形成一个进化保守的信号盒，用于控制许多组织中的PCP。脂肪也是上皮细胞增殖的负调节因子。缺乏脂肪的细胞表现为增生性生长。尽管这一关键作用，但对脂肪在生长控制中的调节或功能知之甚少。我们建议通过以下途径来研究脂肪的作用：1)研究分级的Four-jointed， Dachsous和Fat活性在确定PCP方向中的作用；2)研究Four-jointed和Dachsous在控制细胞增殖过程中调节脂肪的能力；3)确定脂肪控制PCP和增殖的下游途径；4)确定脂肪是如何被Four-jointed和Dachsous调节的。这些实验将为PCP和生长控制以及原钙粘蛋白的功能提供新的见解，原钙粘蛋白与Usher综合征听力障碍和肝癌和结肠癌的肿瘤抑制有关。

DESCRIPTION (provided by applicant): Epithelial planar cell polarity (PCP) is present when the cells of a tissue are all polarized along a uniform axis lying in the plane of the epithelium. Physiologically important examples of PCP are found in many vertebrate tissues including the respiratory system, where ciliated cells must be polarized in a uniform direction for their beating to drive mucus from the lungs, and the ear, where the sensory hair cells must be polarized in a uniform direction so that their stereocilia are correctly arrayed to respond to sound. Among the most important questions regarding PCP is how individual cells sense the proper direction in which to polarize. Previous studies in Drosophila have provided a partial answer to this question by showing that cells respond to Frizzled, a transmembrane receptor protein, whose activity is present in a gradient across the tissue. However, Frizzled is not itself expressed in a graded fashion and the mechanisms used to establish the Frizzled signaling gradients are poorly understood. In a recent study of PCP in the Drosophila eye, we demonstrated that Fat, a protocadherin protein, is essential for establishing the Frizzled activity gradient that directs PCP. We also showed that Fat is regulated during this process by Dachsous (another protocadherin) and Four-jointed (a transmembrane protein). We further suggested that Fat, Dachsous and Four-jointed may form an evolutionarily conserved signaling cassette that is used to control PCP in many tissues. Fat is also a negative regulator of epithelial cell proliferation. Cells lacking Fat exhibit hyperplasic growth. Despite this critical role, little is known about the Fat regulation or function during growth control. We propose to study the role of Fat by: 1) examining the roles of graded Four-jointed, Dachsous and Fat activity in specifying the direction of PCP, 2) examining the ability of Four-jointed and Dachsous to regulate Fat during the control of cell proliferation, 3) identifying the downstream pathways used by Fat to control PCP and proliferation and 4) determining how Fat is regulated by Four-jointed and Dachsous. These experiments should yield new insights into PCP and growth control as well as into the function of protocadherins, which have been implicated in the Usher Syndrome hearing disorders and as tumor suppressors in liver and colon carcinomas.