Cadherin regulation of tissue polarity and growth

钙粘蛋白调节组织极性和生长

• 批准号: 7009980
• 负责人: MICHAEL A SIMON
• 金额: $ 30.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009980
• 关键词: Drosophilidae; arthropod genetics; cadherins; cell proliferation; cell surface receptors; cellular polarity; compound eye; developmental genetics; epithelium; histogenesis

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.

描述（由申请人提供）：当组织的细胞全部沿着位于上皮平面内的统一轴极化时，就存在上皮平面细胞极性（PCP）。 在生理学上重要的五氯苯酚例子存在于许多脊椎动物组织中，包括呼吸系统和耳朵，其中纤毛细胞必须沿统一方向极化才能跳动以将粘液从肺部排出，而耳朵中感觉毛细胞必须沿统一方向极化，以便其静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知正确的极化方向。 先前对果蝇的研究已经为这个问题提供了部分答案，表明细胞对卷曲蛋白（一种跨膜受体蛋白）有反应，其活性在整个组织中呈梯度存在。 然而，卷曲本身并不以分级方式表达，并且用于建立卷曲信号梯度的机制知之甚少。 在最近对果蝇眼中 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 的卷曲活性梯度至关重要。 我们还表明，在此过程中脂肪受到 Dachsous（另一种原钙粘蛋白）和四关节蛋白（一种跨膜蛋白）的调节。 我们进一步提出，Fat、Dachsous 和四关节可能形成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剂。 缺乏脂肪的细胞表现出增生性生长。 尽管具有这一关键作用，但人们对脂肪在生长控制过程中的调节或功能知之甚少。我们建议通过以下方式研究脂肪的作用：1）检查分级的四关节、Dachsous 和 Fat 活性在指定 PCP 方向中的作用，2）检查四关节和 Dachsous 在控制细胞增殖过程中调节 Fat 的能力，3）确定 Fat 用于控制 PCP 和增殖的下游途径，4）确定四关节和 Dachsous 如何调节 Fat。 这些实验应该会对 PCP 和生长控制以及原钙粘蛋白的功能产生新的见解，原钙粘蛋白与亚瑟综合症听力障碍以及肝癌和结肠癌中的肿瘤抑制因子有关。