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（申请人提供）：上皮细胞通常以两个轴极化，在基上基轴和上皮平面内的第二个轴，通常称为 平面CEL极性（或PCP）。哺乳动物中PCP的经典示例包括具有芽方向或内部器官内部器官的细胞排列的皮肤发育方面，例如内耳上皮及其感觉纤毛。在果蝇中，所有成年表皮结构都显示PCP特征。果蝇中PCP建立的研究是发育模式和疾病中PCP建立的范例。果蝇中的分析已经建立了一个保守的分子盒，并锚定在卷曲的（FZ）跨膜蛋白和相关调节因子周围。这种FZ/PCP信号通路及其核心调节成分在整个演化过程中都保守，不仅在上皮器官中，而且在哺乳动物胃肠道和神经化过程中，调节细胞极化的许多方面。尽管核心FZ/PCP因子之间细胞内相互作用的分子机制开始被理解，但对于远程PCP调节的机制众所周知，在整个器官之间协调极性。此应用的范围是跟进有趣的观察结果，这些观察结果表明，远程PCP配位要求FZ蛋白（通常是Wnt-Family型配体的受体）作为配体本身，从而激活新的信号通路，通过与四体跨膜受体van Gogh（Vang; Vang; Vang; Vang; Mammals in Mammals）结合来激活新的信号途径。基于有趣的初步数据，我们提出了特定的目的，旨在识别并开始组装这一新颖途径，并在Vang下游作用。我们已经建立了几种测定方法，可以使我们能够解决这一点：将在果蝇和CEL培养的生化分析中进行全基因组遗传研究的结合以实现我们的目标。由于全球长范围的PCP型极化事件在很大程度上是晦涩的，因此我们的应用将为Vang信号途径的机理提供第一个洞察力，该机制在FZ结合的下游解释远距离提示的下游。 PCP的建立和FZ-VANG因素与几种医学异常有关，包括耳聋，癌症（途径的几个组成部分是原始癌基因或肿瘤抑制剂），多性囊性肾脏疾病和纤毛病。因为，在本应用程序中获得的这样的信息既可以提高我们对PCP和器官模式的理解，并且在几种疾病的情况下也将具有医学相关性。 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几种疾病有关，从癌症到纤毛病和耳聋。虽然PCP的细胞方面已开始被理解，但该过程的远程调节仍然晦涩难懂。该应用程序的范围是确定远程PCP调节所需的组件。这里获得的信息对于多种医疗疾病具有很高的意义。