Non-canonical Wnt Signals in Kidney Tubulogenesis

描述(由申请人提供)：WNT信号通路对于脊椎动物的轴规范、身体模式和器官发生是必不可少的。这些途径包括Wnt配体与Frizzled型受体的结合，以激活“正则”(p-catenin/Tcf/Lef介导)和“非正则”效应。两栖动物和哺乳动物的肾小管形成都需要Wnt信号(Saulnier et.艾尔2002年，斯塔克等人。艾尔1994年，和Carroll et.艾尔2005)。最近的研究表明，规范信号参与了肾小管的发育。然而，非典型信号在小管发育中的作用还没有被研究过。建立平面细胞极性(PCP)的非规范Wnt信号的缺陷可能导致囊性肾脏疾病的发育缺陷，包括多囊肾疾病和肾单位肾炎。这项建议评估了非规范的Wnt信号在非洲爪哇两栖动物系统中肾小管形态发生中的可能作用。非洲爪哇提供了许多实验优势，包括方便地引入外源结构来阻断或激活信号通路(允许救援分析)，快速发育和易于观察到表面外胚层下形成的肾脏。使用转基因和其他方法，将评估平面细胞极性(PCP)以及钙介导的非典型Wnt途径分支在肾小管形成中的作用。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的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，异常的Wnt信号会导致人类肾脏疾病，如多囊肾病、肾癌和肾单位肾炎。本研究以蛙肾为模型，重点研究Wnt信号在肾脏发育中的作用。这项工作测试了Wnt信号通路的特定组件，即所谓的“非规范”Wnt信号，是否是肾脏发育所必需的，以及这些信号的干扰是否会导致异常的肾脏形成和可能的病理背景下的疾病。

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.