Planar Cell Polarity regulation by transmembrane proteins

上皮细胞的极化有两个轴，一个是普遍存在的顶端-基底极性，另一个是第二轴 在上皮平面内，后者称为平面细胞极性（或PCP）。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 在果蝇和一般昆虫中，所有的表皮结构和复眼。同样，在哺乳动物中， 五氯苯酚在哺乳动物的皮肤、内耳上皮及其感觉纤毛或呼吸道上皮中表现明显。 系统和几乎所有其他内部器官。此外，在原肠胚形成过程中， 神经管的形成和闭合需要PCP信号。五氯苯酚在果蝇体内的建立是 研究这种发展和疾病中的极性的范例。PCP由远程信号协调 从Wnt，导致卷曲（Fz）受体的不对称定位（与Wnt家族成员作为其 配体）及其相关的信号级联。解释极性需要岩心Fz/PCP系数 并将其中继到相邻小区。核心Fz/PCP组的所有成员都是保守的 并调节协调细胞极化的所有PCP方面。Wnt-Fz/PCP信令是 与经典的Wnt-Fz/β-catenin途径不同（以及正确调节 由相同受体激活的两条Wnt途径对发育和疾病至关重要）。在五氯苯酚中- 信号传导Fz既作为Wnt的受体又作为其细胞间结合伴侣旺/Stbm的配体 （哺乳动物中的Vangl 1/2）。在Fz结合时作用于旺/Vangl下游的细胞机制是 未知本申请的范围和重点是调查机制和监管的相互作用 由于这些细胞间的相互作用，以及它们在核心PCP中的整合， 互动框架根据令人兴奋的初步数据，我们提出的具体目标是：（1）建立 Fz诱导的旺磷酸化和相关激酶功能的生理意义，（2） 从功能上剖析了旺/Vangl及其细胞质效应物的分子相互作用，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辅助，以及（3）定义 新的分子和细胞机制作为下游的旺的反应，其细胞间Fz相互作用。一 结合果蝇体内研究、小鼠皮肤细胞和果蝇细胞的细胞培养分析，以及 将进行生化实验以实现这些目标。翻译后修饰事件将 要特别注意。PCP的建立和Wnt/Fz信号传导的过程已经被链接到 几种医学异常，从耳聋到脊柱裂/神经管闭合缺陷，以及癌症， 或多囊性肾病和一般的纤毛病。在这里获得的信息将有助于我们 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.