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.
|Valls, Gabriela; Codina, Montserrat; Miller, Rachel K et al. (2012) Upon Wnt stimulation, Rac1 activation requires Rac1 and Vav2 binding to p120-catenin. J Cell Sci 125:5288-301|
|Miller, Rachel K; Canny, Sol Gomez de la Torre; Jang, Chuan-Wei et al. (2011) Pronephric tubulogenesis requires Daam1-mediated planar cell polarity signaling. J Am Soc Nephrol 22:1654-64|
|Miller, Rachel K; McCrea, Pierre D (2010) Wnt to build a tube: contributions of Wnt signaling to epithelial tubulogenesis. Dev Dyn 239:77-93|
|Lyons, Jon P; Miller, Rachel K; Zhou, Xiaolan et al. (2009) Requirement of Wnt/beta-catenin signaling in pronephric kidney development. Mech Dev 126:142-59|