Non-canonical Wnt Signals in Kidney Tubulogenesis

肾小管发生中的非典型 Wnt 信号

• 批准号: 7669089
• 负责人: Rachel Katherine Miller
• 金额: $ 5.01万
• 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/7669089
• 关键词: Address; Amphibia; Animal Model; Binding; Body Patterning; Calcium; Cell Polarity; Cells; Code; Cystic Kidney Diseases; Defect; Development; Developmental Process; Disease; Distal; Duct (organ) structure; Human; Imagery; Kidney; Kidney Diseases; Ligands; Maintenance; Mammals; Mediating; Mesenchyme; Modeling; Monomeric GTP-Binding Proteins; Morphogenesis; Nephronophthisis; Nephrons; 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范，身体图案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“规范”（p-catenin/tcf/lef介导）和“非典型”效应子。两栖动物和哺乳动物中的肾小管形成都需要Wnt信号传导（Saulnier等，2002，Stark等，1994，以及Carroll等，2005）。最近的工作表明，规范信号与肾小管发育有关。然而，尚未研究非规范信号传导在小管发育中的作用。建立平面细胞极性（PCP）的非典型WNT信号传导的缺陷可能导致囊性肾脏疾病的发育缺陷，包括多囊性肾脏疾病和肾持续性。该提案评估了非传统Wnt信号传导在Xenopus laevis两栖动物系统中的肾小管形态发生中的可能作用。 Xenopus提供了许多实验优势，包括易于引入外源构建体以阻止或激活信号通路（允许救援分析），快速发育以及表面外胚层下形成肾脏的易于可视化。使用转基因和其他方法，将评估平面细胞极性（PCP）的作用，以及肾小管微管发生中非canonicalwnt途径的钙​​介导的分支。总体而言，这项工作将提供确定非典型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信号在肾脏发育中很重要，并且异常的WNT信号导致人类肾脏疾病，例如多囊性肾脏病，肾脏癌和肾持续性疾病。该提案的重点是了解使用青蛙肾脏作为模型的Wnt信号在肾脏发育中的作用。这项工作测试Wnt信号通路的特定组件（称为“非典型” Wnt信号）是否需要肾脏发育以及这些信号的破坏是否会导致肾脏形成异常和可能在病理环境中的疾病。