Non-canonical Wnt Signals in Kidney Tubulogenesis

肾小管发生中的非典型 Wnt 信号

• 批准号: 7545595
• 负责人: Rachel Katherine Miller
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545595
• 关键词: Address; Amphibia; Animal Model; Binding; Body Patterning; Calcium; Cell Polarity; Cells; Code; Cystic Kidney Diseases; Defect; Development; Developmental Process; Disease; Disruption; Distal; Duct (organ) structure; Human; Imagery; Kidney; Kidney Diseases; Ligands; Maintenance; Malignant neoplasm of kidney; Mammals; Mediating; Mesenchyme; Modeling; Monomeric GTP-Binding Proteins; Morphogenesis; Nephronophthisis; Nephrons; Numbers; Organogenesis; Pathologic; Pathway interactions; Play; Polycystic Kidney Diseases; Process; Pronephric structure; Proteins; Rana; Renal carcinoma; Renal tubule structure; Research; Role; Signal Pathway; Signal Transduction; Structure; Surface Ectoderm; System; Testing; Transgenic Organisms; Work; Xenopus; Xenopus laevis; cell motility; embryo stage 2; in vivo; interest; mutant; nephrogenesis; novel; receptor

DESCRIPTION (provided by applicant): Wnt signaling pathways are essential to vertebrate axis specification, body patterning, and organogenesis. These pathways involve the binding of Wnt ligands to Frizzled receptors to activate "canonical" (p-catenin/Tcf/Lef mediated) and "non-canonical" effectors. Renal tubule formation in both amphibians and mammals requires Wnt signaling (Saulnier et. al. 2002, Stark et. al. 1994, and Carroll et. al. 2005). Recent work suggests that canonical signaling is involved in nephric tubule development. However, the role of non-canonical signaling in tubule development has not been examined. Deficiencies in non-canonical Wnt signaling, which establishes planar cell polarity (PCP), may contribute to the developmental defects underlying cystic kidney diseases including polycystic kidney disease and nephronophthisis. This proposal assesses the possible roles of non-canonical Wnt signaling in kidney tubule morphogenesis in the Xenopus laevis amphibian system. Xenopus offers a number of experimental advantages including the facile introduction of exogenous constructs to block or activate signaling pathways (permitting rescue analysis), rapid development and easy visualization of the forming kidney under the surface ectoderm. Using transgenic and additional approaches,the roles of the planar cell polarity (PCP) as well as the calcium-mediated branches of the non-canonicalWnt pathway in kidney tubulogenesis will be assessed. Overall, this work will provide the possibility of determining the relevance of non-canonical Wnt signals to kidney development and likely disease. Relevance: Recent evidence suggests that Wnt signaling is important in kidney development and that abnormal Wnt signaling results in human kidney diseases, such as polycystic kidney disease, kidney cancer, and nephronophthisis. This proposal focuses on understanding the roles of Wnt signaling in kidney development using the frog kidney as a model. This work tests whether specific components of the Wnt signaling pathway, called "non-canonical" Wnt signals, are required for kidney development and whether disruption of these signals will result in aberrant kidney formation and likely disease in pathologic contexts.

描述（由申请人提供）：Wnt 信号通路对于脊椎动物轴规格、身体模式和器官发生至关重要。这些途径涉及 Wnt 配体与卷曲受体的结合，以激活“经典”（p-连环蛋白/Tcf/Lef 介导）和“非经典”效应器。两栖动物和哺乳动物的肾小管形成都需要 Wnt 信号传导（Saulnier et. al. 2002、Stark et. al. 1994 和 Carroll et. al. 2005）。最近的研究表明，经典信号传导参与肾小管的发育。然而，非规范信号在肾小管发育中的作用尚未得到研究。建立平面细胞极性 (PCP) 的非经典 Wnt 信号传导缺陷可能导致囊性肾病（包括多囊肾病和肾痨）的发育缺陷。该提案评估了非规范 Wnt 信号在非洲爪蟾两栖动物系统肾小管形态发生中的可能作用。非洲爪蟾具有许多实验优势，包括轻松引入外源构建体来阻断或激活信号通路（允许救援分析）、快速发育以及表面外胚层下正在形成的肾脏的轻松可视化。使用转基因和其他方法，将评估平面细胞极性（PCP）以及非经典 Wnt 通路的钙介导分支在肾小管发生中的作用。总体而言，这项工作将提供确定非规范 Wnt 信号与肾脏发育和可能疾病的相关性的可能性。相关性：最近的证据表明，Wnt 信号传导在肾脏发育中很重要，异常的 Wnt 信号传导会导致人类肾脏疾病，例如多囊肾病、肾癌和肾痨。该提案的重点是使用青蛙肾脏作为模型来了解 Wnt 信号传导在肾脏发育中的作用。这项工作测试了肾脏发育是否需要 Wnt 信号通路的特定成分（称为“非规范”Wnt 信号），以及这些信号的破坏是否会导致肾脏形成异常和病理情况下可能发生疾病。