The Wilms tumor genes wt1a and wt1b control different steps during formation of the zebrafish pronephros

The Wilms tumor protein WT1 is an essential factor for kidney development. In humans, mutations in WT1 lead to Wilms tumor, a pediatric kidney cancer as well as to developmental anomalies concerning the urogenital tract. Inactivation of Wt1 in mice causes multiple organ defects most notably agenesis of the kidneys. In zebrafish, two paralogous wt1 genes exist, wt1a and wt1b. The wt1 genes are expressed in a similar and overlapping but not identical pattern. Here, we have examined the role of both wt1 genes in early kidney development employing a transgenic line with pronephros specific GFP expression and morpholino knockdown experiments. Inactivation of wt1a led to failure of glomerular differentiation and morphogenesis resulting in a rapidly expanding general body edema. In contrast, knockdown of wt1b was compatible with early glomerular development. After 48 h, however, wt1b morphant embryos developed cysts in the region of the glomeruli and tubules and subsequent pericardial edema at 4 days post-fertilization. Thus, our data suggest different functions for wt1a and wt1b in zebrafish nephrogenesis. While wt1a has a more fundamental and early role in pronephros development and is essential for the formation of glomerular structures, wt1b functions at later stages of nephrogenesis.     

Genetische Prädisposition für Wilms-Tumor

Wilms tumor (WT) is an embryonal tumor of the kidney and is due to aberrant proliferation of early precursor cells. WT1 mutations are found in 10–15% of WT. The WT1 gene has a function during normal kidney and genital development. Germline mutations in this gene are found in patients with urogenital abnormalities, isolated nephrotic syndrome, Denys Drash syndrome, Frasier syndrome, WAGR syndrome (Wilms tumor, aniridia, genital malformation, and mental retardation), and some rare cases of familial WT. These patients are at high risk of unilateral WT, and also of synchronous or metachronous bilateral WT, which may occur later in life. An elevated risk of WT is also observed in some overgrowth syndromes, various tumor predisposition syndromes, and specific constitutional aneuploidies. Embryonal tumors develop during early phases of development when cells still have a high doubling rate. Aberrations that delay or inhibit the switch from proliferation to differentiation lead to an expanded cell pool, in which further mutations can occur in various genes that regulate this process. This may explain the heterogeneous diseases/genetic aberrations that are associated with an elevated risk of WT.     

WT1 and glomerular function

The Wilms' Tumour 1 (WT1) gene plays an important role at three different stages of kidney development. The onset of kidney formation, the progression of kidney formation and the maintenance of normal kidney function. Disruption of WT1 may lead to a whole spectrum of kidney diseases ranging from tumour development to mild forms of renal failure. However, the underlying mechanisms are largely unknown. The WT1 proteins have been implicated in various cellular processes like proliferation, differentiation and apoptosis and in agreement with these diverse functions, the number of target genes is still mounting. The development of mouse models in recent years has contributed considerably to a better understanding of the biological activities of WT1, and in this article we will discuss the role of WT1 during kidney formation and kidney function.     

Mammalian Kidney Development: Principles,Progress, and Projections

The mammalian kidney is a vital organ with considerable cellular complexity and functional diversity. Kidney development is notable for requiring distinct but coincident tubulogenic processes involving reciprocal inductive signals between mesenchymal and epithelial progenitor compartments. Key molecular pathways mediating these interactions have been identified. Further, advances in the analysis of gene expression and gene activity, coupled with a detailed knowledge of cell origins, are enhancing our understanding of kidney morphogenesis and unraveling the normal processes of postnatal repair and identifying disease-causing mechanisms. This article focuses on recent insights into central regulatory processes governing organ assembly and renal disease, and predicts future directions for the field.     

Modulation of EGF receptor autophosphorylation by alpha-hemolysin of Staphylococcus aureus via protein tyrosine phosphatase

In the present study we have demonstrated that WT1 (Wilms tumor suppressor gene) enhances the expression of TauT (taurine transporter gene) in human embryonic kidney 293 cells in a dose-dependent manner. TauT promoter activity was increased five-fold by cotransfection of a full-length TauT promoter–reporter construct with WT1. Electrophoretic mobility shift assays (EMSAs) using nuclear extracts from WT1-overexpressing 293 cells showed a putative WT1-binding site in the basal promoter region of TauT, which bound to WT1 in EMSAs. Mutation of this WT1 consensus sequence abolished binding of WT1. These results demonstrate that TauT may represent a downstream target gene of WT1 during renal development.     

The Wilms' tumor gene WT1 is a common marker of progenitor cells in fetal liver

It is well known that the Wilms' tumor gene WT1 plays an important role in cell proliferation and differentiation, and in organ development. In this study, to examine the role of the WT1 gene in lineage determination, fetal liver cells from LacZ-transgenic mice, in which WT1 expression was marked by the expression of the LacZ gene driven by WT1 promoter, were FACS-sorted according to LacZ expression of high (LacZ(++)) or undetectable (LacZ(-)) levels, which paralleled endogenous WT1 expression levels. LacZ(++) fetal liver cells were enriched by hepatocyte and endothelial progenitor cells. These results indicated that WT1 expression is a common marker of both hepatocyte and endothelial progenitors. These results also implied a role of the WT1 gene in lineage determination.