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轴特化、身体模式化和器官发生是必不可少的。这些途径涉及Wnt配体与Frizzled受体的结合以激活“经典”（β-连环蛋白/Tcf/Lef介导的）和“非经典”效应物。两栖动物和哺乳动物中的肾小管形成需要Wnt信号传导（Saulnier et.等人，2002，Stark et.等人，1994和卡罗尔等人，2005）。最近的工作表明，经典信号参与肾小管发育。然而，非典型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信号传导中的缺陷可能导致囊性肾病（包括多囊肾病和肾单位营养不良）的潜在发育缺陷。该建议评估了非经典Wnt信号在非洲爪蟾两栖动物系统中肾小管形态发生中的可能作用。非洲爪蟾提供了许多实验优势，包括容易引入外源性构建体来阻断或激活信号传导途径（允许救援分析），快速发育和容易观察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）以及非经典Wnt途径的钙介导分支在肾小管发生中的作用。总的来说，这项工作将提供确定非经典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是重要的，并且异常的Wnt信号传导导致人类肾脏疾病，例如多囊肾病、肾癌和肾单位肾结核。本研究以蛙肾为模型，探讨Wnt信号在肾脏发育中的作用。这项工作测试了Wnt信号通路的特定成分，称为“非经典”Wnt信号，是否是肾脏发育所需的，以及这些信号的破坏是否会导致异常肾脏形成和病理背景下的可能疾病。

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.