PCP in vertebrate epithelial tubes

脊椎动物上皮管中的 PCP

• 批准号: 8461699
• 负责人: Jeffrey D. Axelrod
• 金额: $ 46.89万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-18 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461699
• 关键词: Address; Adult; Apical; Biological Models; Caliber; Cell Polarity; Cell division; Cells; Cilia; Congenital Heart Defects; Cues; DNA Sequence Rearrangement; Data; Defect; Development; Developmental Process; Disease; Distal; Drosophila genus; Elements; Epithelial; Epithelial Cells; Epithelium; Etiology; Feedback; Filopodia; Genetic; Hair Cells; In Vitro; Knowledge; Light; Microtubules; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Movement; Movement Disorders; Mus; Neoplasm Metastasis; Neural tube; Organ of Corti; Pathogenesis; Physiological; Polycystic Kidney Diseases; Primary Ciliary Dyskinesias; Process; Proteins; Pulmonary Hypertension; Recruitment Activity; Renal tubule structure; Role; Sensory Hair; Side; Signal Transduction; Staging; Stereocilium; System; Tissues; Trachea; Transport Vesicles; Tube; Vertebrates; base; cancer cell; deafness; fly; in vivo; kinetosome; migration; mortality; novel; receptor; therapy development

DESCRIPTION (provided by applicant): The cells in many epithelia are polarized along an axis orthogonal to their apical-basal axis. This polarization, referred to as Planar Cell Polarity (PCP), is necessary for numerous developmental processes and physiological functions. In vertebrates, disruption of these processes gives rise to a variety of developmental defects and disease states. Studies in the fruit fly, Drosophila, have produced an emerging understanding of the molecular mechanisms controlling PCP, and strong evidence indicates conservation of key elements of this mechanism in at least some vertebrate tissues, although novel, vertebrate specific elements have also been identified. In both flies and vertebrates, molecular polarization, based on a common mechanism, produces a variety of morphologic manifestations. Among these are the orientations of multiciliated cells in the upper airway so that their cilia beat in the correct direction and the orientation of renal tubule cells that enables them to undergo directional rearrangement and oriented cell divisions that regulate and maintain tubule diameter. Genetic and molecular analyses in Drosophila have identified components of the PCP signaling mechanism, and have led to an emerging understanding of the mechanism by which they interpret and communicate polarity information. The mechanism leads to the collective molecular polarization of cells, in which a set of conserved PCP proteins communicate at cell boundaries, recruiting one subset of these proteins to the distal side of cells, and another subset to the proximal side, thereby aligning the polarity of adjacent cells. These proteins also produce localized signals that orient the various effectors of morphological polarization. Evidence is emerging to suggest that a conserved group of proteins polarizes and aligns cells with each other in some vertebrate epithelia, although scant mechanistic data exist. There is relatively little knowledge of the signal(s) that serve to globally orient PCP in vertebrates, or if this mechanism is conserved from flies. Furthermore, vertebrate PCP depends on elements not used in flies. Wnt signals are essential in vertebrate PCP, though the best evidence indicates no role for Wnts in Drosophila PCP, and primary cilia are implicated in vertebrate PCP, yet primary cilia are absent in most fly tissues. Finally, little is known about how vertebrate tissues use the PCP signal to execute polarized morphological differentiation. We will address these questions using a powerful combination of in vivo genetic and in vitro culture models of PCP in two mouse epithelial tubes: the multiciliated epithelium of the trachea and the renal tubule. Together, these studies will increase our knowledge of the shared signaling mechanisms that regulate vertebrate PCP, thereby shedding light on the etiology of a range of PCP-dependent developmental anomalies and disease processes. They will also help us to understand in greater detail two specific PCP-dependent diseases, including a class of Primary Ciliary Dyskinesia syndromes and polycystic kidney disease.

描述（由申请人提供）：许多上皮细胞沿与其顶基轴正交的轴沿着极化。这种极化，被称为平面细胞极性（PCP），是许多发育过程和生理功能所必需的。在脊椎动物中，这些过程的中断引起各种发育缺陷和疾病状态。对果蝇（Drosophila）的研究使人们对控制五氯苯酚的分子机制有了新的认识，有力的证据表明，这一机制的关键要素至少在某些脊椎动物组织中得到了保护，尽管也发现了新的脊椎动物特有要素。在苍蝇和脊椎动物中，基于共同机制的分子极化会产生多种形态表现。其中包括上呼吸道中多纤毛细胞的方向，使它们的纤毛在正确的方向上跳动，以及肾小管细胞的方向，使它们能够进行定向重排和定向细胞分裂，从而调节和维持肾小管直径。果蝇的遗传和分子分析已经确定了PCP信号机制的组成部分，并导致对它们解释和传达极性信息的机制的理解。该机制导致细胞的集体分子极化，其中一组保守的PCP蛋白在细胞边界处进行通信，将这些蛋白的一个子集募集到细胞的远端侧，并将另一个子集募集到近端侧，从而对齐相邻细胞的极性。这些蛋白质还产生定位信号，定向形态极化的各种效应物。有证据表明，在一些脊椎动物上皮细胞中，一组保守的蛋白质使细胞极化并使细胞彼此对齐，尽管存在的机制数据很少。对于在脊椎动物中确定五氯苯酚全球分布的信号，或者这种机制是否在苍蝇中保留下来，人们的了解相对较少。此外，脊椎动物的五氯苯酚依赖于苍蝇不使用的元素。Wnt信号在脊椎动物PCP中是必不可少的，尽管最好的证据表明Wnt在果蝇PCP中没有作用，并且初级纤毛与脊椎动物PCP有关，但初级纤毛在大多数苍蝇组织中不存在。最后，很少有人知道脊椎动物组织如何使用PCP信号来执行极化形态分化。我们将解决这些问题，使用一个强大的组合，在两个小鼠上皮管PCP的体内遗传和体外培养模型：气管和肾小管的多纤毛上皮。总之，这些研究将增加我们对调节脊椎动物PCP的共享信号机制的了解，从而阐明一系列PCP依赖性发育异常和疾病过程的病因。他们还将帮助我们更详细地了解两种特定的PCP依赖性疾病，包括一类原发性纤毛运动障碍综合征和多囊肾病。