The Role of Planar Cell Polarity Signals in Shaping Kidney Tubules

平面细胞极性信号在肾小管塑造中的作用

基本信息

批准号：
8508258
负责人：
Rachel Katherine Miller
金额：
$ 11.35万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2012-09-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508258
关键词：
Address Affect Amphibia Animals Architecture Cell Polarity Cell division Cells Cilia Cystic Kidney Diseases Data Defect Development Disease Docking Embryo Epithelial Epithelium Equilibrium Experimental Models Goals Human Image Imagery Kidney Kidney Diseases Knowledge Lead Life Link Maintenance Malignant Neoplasms Mammals Mediating Mesenchyme Methods Modeling Molecular Target Monomeric GTP-Binding Proteins Morphogenesis National Institute of Diabetes and Digestive and Kidney Diseases Nephroblastoma Nephronophthisis Nephrons Organ Outcome Pathogenesis Pathology Pathway interactions Physical condensation Play Polycystic Kidney Diseases Process Publications Publishing Rana Regulation Renal Cell Carcinoma Renal carcinoma Renal tubule structure Research Project Grants Research Support Role Shapes Signal Pathway Signal Transduction Strabismus Sum Surface Ectoderm System Techniques Testing Tissues Transgenic Animals Transgenic Organisms Tube Vision Work Xenopus Xenopus laevis Zebrafish base beta catenin cell motility cilium biogenesis directional cell innovation insight kinetosome neoplastic cell nephrogenesis novel research study

项目摘要

DESCRIPTION (provided by applicant): Formation of renal tubules in both mammals and amphibians requires Wnt pathways. In kidney, aberrant Wnt signaling has been linked to developmental pathologies such as Wilms tumor and cystic diseases, as well as with renal cell carcinoma. Recent studies from our group and others indicate that canonical (?-catenin- mediated) Wnt signaling is essential for induction of nephron development. Additionally, studies suggest that primary cilia are required for a switch from canonical to non-canonical Wnt signaling, and that defects in primary cilia formation or signaling lead to cystogenesis. Varied tissues undergoing morphogenesis employ non-canonical Wnt (PCP: "planar cell polarity") pathways to promote processes including cell polarization and cytoskeletal modulation. Deficiencies in non-canonical Wnt signaling, which contributes to PCP, underlie a number of developmental or later defects, such as polycystic kidney disease and nephronophthisis. Using Xenopus laevis (frog) embryos, supplemented in some contexts with embryos of Danio rerio (zebrafish), this proposal first assesses the roles of non-canonical Wnt PCP components in kidney tubule morphogenesis. Our hypothesis is that the PCP components Daam1, WGEF, Prickle and Strabismus are required for primary cilia formation, which is in turn required for nephric morphogenesis. Xenopus offers experimental advantages including the facile introduction of exogenous constructs to block or activate signaling pathways, rapid development and easy visualization of the forming kidney under the surface ectoderm. Second, using transgenic approaches, we will address in living animals the role of PCP/ non-canonical Wnt signals in shaping and moving cells that are undergoing/ contributing to kidney tubule morphogenesis. Finally, an over-expression screen will be performed to discover new regulators of tubule formation. Overall, this work is novel in assessing the roles of the PCP components in kidney development; in utilizing transgenic approaches in Xenopus laevis to visualize and/ or target kidney development in living embryos; and in performing an unbiased over- expression screen to reveal additional and likely novel components involved in kidney tubulogenesis. In sum, we will enhance our understanding of kidney morphogenesis, which is likely to be relevant to obtaining insights on later pathologies that arise in humans.

描述（由申请人提供）：哺乳动物和两栖动物中肾小管的形成都需要 Wnt 途径。在肾脏中，异常的 Wnt 信号传导与肾母细胞瘤和囊性疾病以及肾细胞癌等发育病理学有关。我们小组和其他人的最新研究表明，经典（β-连环蛋白介导的）Wnt 信号传导对于诱导肾单位发育至关重要。此外，研究表明初级纤毛是从经典 Wnt 信号转导到非经典 Wnt 信号转导所必需的，并且初级纤毛形成或信号传导的缺陷会导致囊肿发生。经历形态发生的各种组织采用非经典 Wnt（PCP：“平面细胞极性”）途径来促进包括细胞极化和细胞骨架调节在内的过程。非经典 Wnt 信号传导缺陷会导致 PCP，是许多发育或后期缺陷的基础，例如多囊肾病和肾痨。该提案使用非洲爪蟾（青蛙）胚胎，并在某些情况下补充了斑马鱼（Danio rerio）胚胎，首先评估了非规范 Wnt PCP 成分在肾小管形态发生中的作用。我们的假设是，PCP 成分 Daam1、WGEF、Prickle 和 Strabismus 是初级纤毛形成所必需的，而初级纤毛形成又是肾形态发生所必需的。非洲爪蟾具有实验优势，包括轻松引入外源构建体来阻断或激活信号通路、快速发育以及表面外胚层下正在形成的肾脏的容易可视化。其次，使用转基因方法，我们将在活体动物中研究 PCP/非规范 Wnt 信号在塑造和移动正在经历/促进肾小管形态发生的细胞中的作用。最后，将进行过度表达筛选以发现小管形成的新调节因子。总体而言，这项工作在评估 PCP 成分在肾脏发育中的作用方面是新颖的。利用非洲爪蟾的转基因方法来可视化和/或瞄准活体胚胎中的肾脏发育；并进行公正的过度表达筛选，以揭示参与肾小管发生的其他且可能新颖的成分。总之，我们将增强对肾脏形态发生的理解，这可能与获得对人类后来出现的病理学的见解相关。