Cadherin regulation of tissue polarity and growth

描述(申请人提供)：当一个组织的细胞都沿着位于上皮平面上的一个统一的轴被极化时，就出现了上皮平面细胞极性(PCP)。在许多脊椎动物组织中都发现了PCP的生理上的重要例子，包括呼吸系统和耳朵，在呼吸系统中，纤毛细胞必须以统一的方向极化，才能将粘液从肺部排出；在耳朵中，感觉毛细胞必须以统一的方向极化，以便它们的立体纤毛正确排列，以对声音做出反应。关于PCP最重要的问题之一是，单个细胞如何感觉到极化的正确方向。以前对果蝇的研究已经提供了这个问题的部分答案，因为它表明细胞对Frizzled型跨膜受体蛋白有反应，这种蛋白的活性在整个组织中呈梯度分布。然而，Frizzled本身并不是以分级的方式表达的，用于建立Frizzled信号梯度的机制也鲜为人知。在最近对果蝇眼内PCP的研究中，我们证明了Fat是一种原钙粘蛋白蛋白，对于建立引导PCP的Frizzled活动梯度是必不可少的。我们还发现，在这一过程中，脂肪受到Dachsous(另一种原钙粘附素)和四关节(一种跨膜蛋白)的调节。我们进一步认为，Fat、Dachsous和四关节可能形成了一个进化上保守的信号盒，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。缺乏脂肪的细胞呈增生性生长。尽管有这一关键作用，但人们对脂肪调节或在生长控制中的作用知之甚少。我们建议通过以下几个方面来研究Fat的作用：1)研究分级的四关节、Dachsous和Fat活性在决定PCP的方向中的作用；2)检测Fat在控制细胞增殖过程中调节Fat的能力；3)确定Fat控制PCP和增殖的下游途径；以及4)确定Fat是如何通过四关节和Fachsous来调节Fat的。这些实验应该会对PCP和生长控制以及原钙粘附素的功能产生新的见解，这些原钙粘附素与Usher综合征听力障碍有关，并在肝癌和结肠癌中作为肿瘤抑制因子。

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.