Cadherin regulation of tissue polarity and growth

钙粘蛋白调节组织极性和生长

• 批准号: 6717491
• 负责人: MICHAEL A SIMON
• 金额: $ 30.66万
• 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/6717491
• 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）：当组织细胞全部沿位于上皮平面内的均匀轴沿着极化时，存在上皮平面细胞极性（PCP）。 PCP在许多脊椎动物组织中发现了生理上重要的例子，包括呼吸系统，其中纤毛细胞必须以统一的方向极化，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以统一的方向极化，以便它们的静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正确的方向。 以前在果蝇中的研究已经为这个问题提供了部分答案，表明细胞对Frizzled有反应，Frizzled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本身并不以分级的方式表达，并且用于建立Frizzled信号梯度的机制知之甚少。 在最近的一项关于果蝇眼睛中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，在这一过程中，脂肪是由Dachsous（另一种原钙粘蛋白）和Four-jointed（一种跨膜蛋白）调节的。 我们进一步表明，脂肪，Dachsous和四节可能形成一个进化上保守的信号盒，用于控制PCP在许多组织。脂肪也是上皮细胞增殖的负调节因子。 缺乏脂肪的细胞呈现增生性生长。 尽管这一关键作用，很少有人知道脂肪的调节或功能在生长控制。我们建议通过以下方式研究脂肪的作用：1）检查分级的Four-jointed、Dachsous和Fat活性在指定PCP方向中的作用，2）检查Four-jointed和Dachsous在控制细胞增殖期间调节脂肪的能力，3）确定Fat用于控制PCP和增殖的下游途径，以及4）确定Four-jointed和Dachsous如何调节脂肪。 这些实验应产生新的见解PCP和生长控制以及原钙粘素的功能，这已牵连在Usher综合征听力障碍和肝癌和结肠癌的肿瘤抑制因子。