WT1 regulates the expression of the major glomerular podocyte membrane protein Podocalyxin Journal Article

Authors: Palmer, R. E.; Kotsianti, A.; Cadman, B.; Boyd, T.; Gerald, W.; Haber, D. A.
Article Title: WT1 regulates the expression of the major glomerular podocyte membrane protein Podocalyxin
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.
Keywords: intercellular signaling peptides and proteins; cell proliferation; phenotype; animals; mice; gene targeting; cell cycle; protein binding; membrane proteins; transcription factor; cell differentiation; transcription factors; gene expression regulation; germ line; tumor suppressor gene; membrane protein; cell line, transformed; rats; glycoproteins; 3t3 cells; nephroblastoma; growth substances; zinc fingers; wt1 proteins; kidney cell; kidney glomerulus; podocyte; genes, wilms tumor; humans; sialoglycoproteins; denys drash syndrome; podocalyxin
Journal Title: Current Biology
Volume: 11
Issue: 22
ISSN: 0960-9822
Publisher: Cell Press  
Date Published: 2001-11-13
Start Page: 1805
End Page: 1809
Language: English
DOI: 10.1016/s0960-9822(01)00560-7
PUBMED: 11719225
PROVIDER: scopus
Notes: Export Date: 21 May 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. William L Gerald
    375 Gerald