A Novel Signaling Pathway in Planar Cell Polarity Establishment

平面细胞极性建立中的新型信号通路

• 批准号: 8368456
• 负责人: Marek Mlodzik
• 金额: $ 25.3万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8368456
• 关键词: Address; Adult; Apical; Architecture; Binding; Biochemical; Biological Assay; Boxing; Cartoons; Cell Polarity; Cells; Cilia; Cues; Cystic Kidney Diseases; Data; Development; Disease; Drosophila genus; Epidermis; Epithelial; Epithelial Cells; Epithelium; Event; Evolution; Extracellular Domain; Family; Genes; Genetic; Goals; Hair; Labyrinth; Ligands; Link; Logic; Maintenance; Malignant Neoplasms; Mammalian Oviducts; Mammals; Medical; Membrane; Membrane Proteins; Mesenchymal; Molecular; Morphogenesis; Mus; Mutation; Organ; Pathway interactions; Pattern; Phosphorylation; Phosphotransferases; Process; Proteins; Proto-Oncogenes; Reading; Regulation; Research; Sensory; Signal Pathway; Signal Transduction; Skin; Structure; Tissues; Tumor Suppressor Proteins; Vertebrates; Wing; base; carcinogenesis; cell growth regulation; cell motility; cell type; ciliopathy; deafness; fly; follow-up; gastrulation; genetic regulatory protein; genome wide association study; genome-wide; high risk; in vivo; insight; interest; novel; receptor; response

DESCRIPTION (provided by applicant): Epithelial cells are often polarized in two axes, in the apical-basal axis and in a second axis within the plane of the epithelium, generally referred to as Planar Cel Polarity (or PCP). Classical examples of PCP in mammals include aspects of skin development with hair bud orientation or cellular arrangements in internal organs, like the inner ear epithelium with its sensory cilia. In Drosophila, all adult cuticular structures display PCP features. The study of PCP establishment in Drosophila serves as a paradigm for PCP establishment in developmental patterning and disease. Analyses in Drosophila have established a conserved molecular cassette and pathway anchored around the Frizzled (Fz) trans-membrane protein and associated regulatory factors. This Fz/PCP signaling pathway and its core regulatory components are conserved throughout evolution regulating many aspects of cellular polarization not only in epithelial organs, but also in directed cell migration of mesenchymal cells during mammalian gastrulation and neurulation. Although the molecular mechanisms of the intracellular interactions among the core Fz/PCP factors are beginning to be understood, very little is known about the mechanisms of long-range PCP regulation coordinating polarity across whole organs. The scope of this application is to follow-up on interesting observations that suggest that long-range PCP coordination requires that the Fz protein (generally a receptor for Wnt-family type ligands) acts as a ligand itself, activating a novel signaling pathway by binding to the four-pass trans-membrane receptor Van Gogh (Vang; Vang-like in mammals). Based on interesting preliminary data, we propose as Specific Aims to identify the components of and start assembling this novel pathway, acting downstream of Vang. We have established several assays that will allow us to address this: A combination of genome-wide genetic in vivo studies in Drosophila and cel culture biochemical analyses will be performed to achieve our goals. As the global long- range PCP-type polarization events are largely obscure, our application will provide the first insight(s) into the mechanism of a Vang-signaling pathway that acts downstream of Fz-binding interpreting long-range cues. PCP establishment and the Fz-Vang factors have been linked to several medical abnormalities, including deafness, cancer (several components of the pathway are proto-oncogenes or tumor suppressors), poly cystic kidney disease, and ciliopathies. As, such the information acquired in this application will both advance our understanding of PCP and organ patterning, and will also be of medical relevance in several disease contexts. PUBLIC HEALTH RELEVANCE: Cellular polarity is a critical feature of organ development and function. The establishment and maintenance of epithelial planar cell polarity (PCP) features are linked to several diseases, ranging from cancer to ciliopathies and deafness. Whereas cellular aspects of PCP are beginning to be understood, the long-range regulation of this process remains obscure. The scope of this application is to identify the components required for long-range PCP regulation. The information acquired here is of high significance for several medical disorders.

描述（由申请人提供）：上皮细胞通常在两个轴上极化，即在顶-底轴上和在上皮平面内的第二轴上，通常称为顶-底轴。 平面细胞极性（或PCP）。五氯苯酚在哺乳动物体内的典型例子包括皮肤发育的各个方面，包括毛发芽的定向或内脏器官的细胞排列，如内耳上皮及其感觉纤毛。在果蝇中，所有成年表皮结构显示PCP特征。PCP在果蝇体内建立的研究为PCP在发育模式和疾病中的建立提供了范例。果蝇中的分析已经建立了一个保守的分子盒和锚定在卷曲（Fz）跨膜蛋白和相关调控因子周围的途径。Fz/PCP信号通路及其核心调控成分在整个进化过程中是保守的，不仅在上皮器官中调节细胞极化的许多方面，而且在哺乳动物原肠胚形成和神经胚形成期间间充质细胞的定向细胞迁移中也是如此。虽然核心Fz/PCP因子之间的细胞内相互作用的分子机制开始被理解，但对整个器官的长程PCP调节协调极性的机制知之甚少。本申请的范围是跟踪有趣的观察结果，这些观察结果表明，长距离PCP协调需要Fz蛋白（通常是Wnt家族型配体的受体）本身作为配体，通过与四通道跨膜受体货车Gogh（旺;哺乳动物中的Vang样）结合激活新的信号传导途径。基于有趣的初步数据，我们提出了具体的目标，以确定组件，并开始组装这种新的途径，作用于下游的旺。我们已经建立了几种检测方法，使我们能够解决这个问题：将进行果蝇全基因组遗传体内研究和细胞培养生化分析的组合，以实现我们的目标。由于全局长程PCP型极化事件在很大程度上是模糊的，因此我们的应用将提供对Vang信号传导途径的机制的第一次洞察，所述Vang信号传导途径在Fz结合的下游起作用，解释长程线索。PCP的建立和Fz-Vang因子与几种医学异常有关，包括耳聋、癌症（该途径的几个组成部分是原癌基因或肿瘤抑制因子）、多囊肾病和纤毛病。因此，本应用程序中获得的信息将促进我们对PCP和器官模式的了解，并且在多种疾病背景下也具有医学相关性。 公共卫生相关性：细胞极性是器官发育和功能的关键特征。上皮平面细胞极性（PCP）特征的建立和维持与从癌症到纤毛病和耳聋的几种疾病有关。虽然细胞方面的五氯苯酚开始被理解，这一进程的长期调控仍然模糊。本申请的范围是确定长期五氯苯酚监管所需的组件。这里获得的信息对几种医学疾病具有重要意义。