UI - 11719225
AU - Palmer RE; Kotsianti A; Cadman B; Boyd T; Gerald W; Haber DA
WT1 regulates the expression of the major glomerular podocyte membrane
SO - Curr Biol 2001 Nov 13;11(22):1805-9
AD - Massachusetts General Hospital Cancer Center and Harvard Medical School,
Charlestown, MA 02129, USA.
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 . 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 , 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
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