PCP in vertebrate epithelial tubes

描述(申请人提供)：许多上皮中的细胞沿着与其顶端-基底轴垂直的轴被极化。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，这些过程的中断会导致各种发育缺陷和疾病状态。对果蝇的研究已经对控制PCP的分子机制有了新的理解，强有力的证据表明，至少在一些脊椎动物组织中保存了这一机制的关键元件，尽管也发现了新的脊椎动物特有元件。在苍蝇和脊椎动物中，分子极化基于一个共同的机制，产生不同的形态表现。其中包括上呼吸道多纤毛细胞的定向，使它们的纤毛跳动在正确的方向上，以及使它们能够进行定向重排的肾小管细胞的定向分裂，以调节和维持小管直径。对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，并导致了对它们解释和交流极性信息的机制的新的理解。这种机制导致细胞的集体分子极化，其中一组保守的PCP蛋白在细胞边界通信，将这些蛋白的一个子集招募到细胞的远侧，另一个子集招募到近侧，从而排列相邻细胞的极性。这些蛋白质还产生定位信号，定位形态极化的各种效应器。越来越多的证据表明，在一些脊椎动物的上皮细胞中，一组保守的蛋白质使细胞极化并相互排列，尽管缺乏机制数据。对于脊椎动物中用于全球定位五氯苯酚的信号(S)，或者这一机制是否对苍蝇保守，人们知之甚少。此外，脊椎动物五氯苯酚依赖于苍蝇没有使用的元素。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信号在果蝇PCP中没有作用，初级纤毛与脊椎动物PCP有关，但大多数果蝇组织中没有初级纤毛。最后，关于脊椎动物组织如何利用PCP信号来执行极化形态分化，我们知之甚少。我们将使用PCP体内遗传和体外培养模型的强大组合来解决这些问题，这些模型位于两个小鼠上皮管中：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的共同信号机制的了解，从而揭示一系列依赖PCP的发育异常和疾病过程的病因。它们还将帮助我们更详细地了解两种特定的五氯苯酚依赖型疾病，包括一类原发性睫状肌运动障碍综合征和多囊肾病。

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.