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: 8514671
• 负责人: Marek Mlodzik
• 金额: $ 19.99万
• 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/8514671
• 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.

描述（由申请人提供）：上皮细胞通常在两个轴上极化，即顶底轴和上皮平面内的第二轴，通常称为 平面 Cel 极性（或 PCP）。哺乳动物中五氯苯酚的典型例子包括皮肤发育、毛芽方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，所有成年角质层结构均表现出 PCP 特征。果蝇中 PCP 建立的研究为发育模式和疾病中 PCP 建立提供了范例。对果蝇的分析已经建立了围绕卷曲 (Fz) 跨膜蛋白和相关调节因子的保守分子盒和通路。这种 Fz/PCP 信号通路及其核心调节成分在整个进化过程中都是保守的，不仅在上皮器官中，而且在哺乳动物原肠胚形成和神经形成期间的间充质细胞的定向细胞迁移中调节细胞极化的许多方面。尽管人们开始了解核心 Fz/PCP 因子之间细胞内相互作用的分子机制，但对于协调整个器官极性的长程 PCP 调节机制知之甚少。本申请的范围是跟进有趣的观察结果，这些观察结果表明，长程 PCP 协调需要 Fz 蛋白（通常是 Wnt 家族型配体的受体）本身充当配体，通过与四次跨膜受体 Van Gogh（Vang；哺乳动物中的 Vang 样）结合来激活新的信号传导途径。基于有趣的初步数据，我们提出了具体目标，以识别并开始组装这条作用于 Vang 下游的新途径。我们已经建立了几种分析方法，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结合，以实现我们的目标。由于全球长程 PCP 型极化事件在很大程度上是模糊的，我们的应用将提供对 Vang 信号通路机制的第一个见解，该通路作用于 Fz 结合下游，解释长程线索。 PCP 的建立和 Fz-Vang 因子与多种医学异常有关，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基因）、多囊肾病和纤毛病。因此，在此应用程序中获得的信息不仅将增进我们对 PCP 和器官模式的理解，而且还将在多种疾病背景下具有医学相关性。