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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

基本信息

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
项目类别：
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

项目摘要

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，在顶基轴上，在上皮平面内的第二个轴上，通常称为