Planar Cell Polarity regulation by transmembrane proteins

上皮细胞因其功能而在两个轴上极化，无处不在的尖端-基底端和第二轴 在上皮平面内，后者被称为平面细胞极性(或PCP)。两者，细胞极性和 器官发生过程中有序的细胞模式取决于PCP机制。典型的PCP示例包括 在果蝇和昆虫中，所有的角质结构和复眼。同样，在哺乳动物中 PCP的某些方面在哺乳动物的皮肤、带有感觉纤毛的内耳上皮或呼吸道中都很明显。 系统和几乎所有其他内脏。此外，原肠形成过程中的收敛伸展过程 神经管的构筑和关闭需要PCP信号。果蝇体内PCP的建立是一种 在发育和疾病中研究这种类型的两极的范例。PCP由远程信号协调 来自Wnts，导致FrizzledFZ受体的不对称定位(以WNT家族成员为其 配体)及其相关的信号级联。需要核心FZ/PCP因子来解释极性 在细胞内，并将其转发到相邻细胞。核心FZ/PCP组的所有成员都是保守的 在整个进化过程中，调节协调细胞极化的PCP的所有方面。WNT-FZ/PCP信令是 不同于经典的Wnt-Fz/β-Catenin途径(以及正确调节 由同一受体(S)激活的这两条Wnt通路对发育和疾病至关重要)。在PCP中- 信号FZ既是Wnts的受体，又是其细胞间结合伙伴Vang/Stbm的配体 (哺乳动物为Vangl1/2)。Vang/Vang1下游作用于FZ结合的细胞机制(S)是 未知。本应用的范围和重点是研究机械性和规律性的相互作用 Vang/Vangl作为这些细胞间相互作用的结果，以及它们在核心PCP中的整合 交互框架。基于令人振奋的初步数据，我们建议作为具体目标：(1)建立 FZ诱导的Vang磷酸化及其相关激酶功能的生理意义，(2) 功能解剖Vang/Vangl及其细胞质效应器的分子相互作用，这一过程将 还可以通过包括具有Vangl相关神经管闭合缺陷的患者数据来帮助，以及(3)定义 作为Vang下游对其细胞间Fz相互作用的响应的新的分子和细胞机制。一个 结合果蝇体内研究，小鼠皮肤细胞和果蝇细胞培养分析，以及 为了实现这些目标，将进行生物化学实验。翻译后修改事件将 会受到特别的关注。PCP建立和WNT/FZ信令的过程已链接到 几种医学异常，从耳聋到脊柱裂/神经管闭合缺陷，以及癌症， 或多囊肾病和一般的纤毛疾病。在这里获得的信息将使我们的 了解细胞极化，并在许多疾病背景下提供医学相关性。

Epithelial cells are polarized in two axes for their function, ubiquitous apical-basal polarity and a second axis within the plane of the epithelium, the latter referred to as Planar Cell Polarity (or PCP). Both, cell polarity and ordered cellular patterning during organogenesis depend on PCP mechanisms. Typical PCP examples include in Drosophila, and insects in general, all cuticular structures and the compound eyes. Similarly, in mammals aspects of PCP are evident in mammalian skin, the inner ear epithelium with its sensory cilia, or the respiratory system and almost all other internal organs. Moreover, convergent extension processes during gastrulation and neural tube patterning and closure requires PCP signaling. PCP establishment in Drosophila serves as a paradigm to study this type of polarity in development and disease. PCP is coordinated by long-range signals from Wnts, resulting in asymmetric localization of the Frizzled (Fz) receptor (with Wnt family members as their ligands) and its associated signaling cascade. The core Fz/PCP factors are required to interpret the polarity within the cell and relay it to neighboring cells. All members of the core Fz/PCP group are conserved throughout evolution and regulate all PCP aspects of coordinated cellular polarization. Wnt-Fz/PCP signaling is distinct from the canonical Wnt-Fz/β-catenin pathway (and correct regulation of signaling specificity between the two Wnt-pathways, activated by the same receptor(s), is critical for development and disease). In PCP- signaling Fz acts both, as the receptor for Wnts and a ligand for its intercellular binding partner Vang/Stbm (Vangl1/2 in mammals). The cellular mechanism(s) acting downstream of Vang/Vangl upon Fz binding are unknown. The scope and focus of this application is to investigate the mechanistic and regulatory interactions of Vang/Vangl as a result of these intercellular interactions, and their integration within the core PCP interaction framework. Based on exciting preliminary data, we propose as Specific Aims to (1) establish the physiological significance of Fz-induced Vang phosphorylation and associated kinase function, (2) to functionally dissect the molecular interactions of Vang/Vangl and its cytoplasmic effectors, a process that will also be aided by including patient data with Vangl associated neural tube closure defects, and (3) define a novel molecular and cellular mechanism as a response downstream of Vang to its intercellular Fz interaction. A combination of in vivo studies in Drosophila, cell culture analyses in mouse skin cells and Drosophila cells, and biochemical experiments will be performed to achieve these goals. Post-translational modification events will be given special attention. The processes of PCP establishment and Wnt/Fz signaling have been linked to several medical abnormalities, ranging from deafness to spina bifida/neural tube closure defects, and cancer, or poly-cystic kidney disease and ciliopathies in general. Information acquired here will both advance our understanding of cellular polarization, and provide medical relevance in many disease contexts.