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Abstract
The WT1 tumor suppressor gene encodes a zinc finger transcription factor expressed
in differentiating glomerular podocytes. Complete inactivation of WT1 in the mouse
leads to failure of mesenchymal induction and renal agenesis, an early developmental
phenotype that prevents analysis of subsequent stages in glomerular differentiation
[1]. In humans with Denys-Drash Syndrome, a heterozygous germline mutation in WT1
is associated with specific defects in glomeruli and an increased risk for developing
Wilms Tumor [2,3]. WT1 target genes implicated in cell cycle regulation and cellular
proliferation have been proposed [4], but the link between WT1 function and glomerular
differentiation is unexplained. Here, we show that inducible expression of WT1 in
rat embryonic kidney cell precursors leads to the induction of endogenous Podocalyxin,
the major structural membrane protein of glomerular podocytes, which is implicated
in the maintenance of filtration slits. Binding of WT1 to conserved elements within
the Podocalyxin gene promoter results in potent transcriptional activation, and the
specific expression pattern of Podocalyxin in the developing kidney mirrors that of
WT1 itself. These observations support a role for WT1 in the specific activation of
a glomerular differentiation program in renal precursors and provide a molecular basis
for the glomerulonephropathy that is characteristic of Denys-Drash Syndrome.