Wilms tumor is a pluripotent tumor which arises from embryonic renal precursors and is the most common pediatric kidney tumor and the fourth most common childhood malignancy. The first gene shown to be inactivated in Wilms tumor was the tumor suppressor WT1 and its functional characterization has emphasized the connection between these tumors and renal development. WT1 is essential for kidney development in mice and it is also responsible for genitourinary defects in the WAGR, Denys-Drash and Frasier syndromes. WT1, however, is inactivated in only 5-10% of sporadic Wilms'tumors. Alterations in beta-catenin, insulin-like growth factor 2 (IGF2) and p53 have been described but there are no known specific genetic defects that account for the majority of cases. The candidate for this KO8 award, Dr. Miguel Rivera, has identified and cloned a novel tumor suppressor gene, WTX, which is inactivated in 30% of sporadic Wilms tumor cases. Remarkably, WTX is expressed in a highly regulated pattern that partially overlaps WT1 during kidney development. Thus, by analogy to WT1, WTX is expected be a critical gene in both Wilms tumorigenesis and kidney development. The candidate now proposes to build on these initial results and characterize the functional properties of WTX in renal development.
Aim 1 : To characterize the biochemical properties of WTX. Lentiviral vectors will be used to express WTX at near physiologic levels and to determine associations with other proteins.
Aim 2 : To define the role of WTX in tissue culture models of renal development. The functional consequences of WTX upregulation and downregulation will be assessed in cell culture models of early renal development (RSTEM cells - a pluripotent renal cell line ) and fully differentiated kidney epithelia (a mouse podocyte cell line).
Aim 3 : To characterize the consequences of conditional WTX inactivation in the mouse kidney. A conditional WTX knockout mouse is being generated in collaboration with the laboratory of Dr. Nabeel Bardeesy. As part of this collaboration, the candidate will analyze the phenotype of this mouse in kidney development. It is anticipated that, by furthering our knowledge of early kidney development, this project will have public health applications in pediatric and adult kidney disease, kidney tissue repair and kidney cancer.
|Moisan, Annie; Rivera, Miguel N; Lotinun, Sutada et al. (2011) The WTX tumor suppressor regulates mesenchymal progenitor cell fate specification. Dev Cell 20:583-596|
|Aiden, Aviva Presser; Rivera, Miguel N; Rheinbay, Esther et al. (2010) Wilms tumor chromatin profiles highlight stem cell properties and a renal developmental network. Cell Stem Cell 6:591-602|
|Rothenberg, S Michael; Mohapatra, Gayatry; Rivera, Miguel N et al. (2010) A genome-wide screen for microdeletions reveals disruption of polarity complex genes in diverse human cancers. Cancer Res 70:2158-64|
|Wells, Julie; Rivera, Miguel N; Kim, Woo Jae et al. (2010) The predominant WT1 isoform (+KTS) encodes a DNA-binding protein targeting the planar cell polarity gene Scribble in renal podocytes. Mol Cancer Res 8:975-85|
|Rivera, Miguel N; Kim, Woo Jae; Wells, Julie et al. (2009) The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity. Proc Natl Acad Sci U S A 106:8338-43|