Article

A Novel Wilms Tumor 1 (WT1) Target Gene Negatively Regulates the WNT Signaling Pathway

Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2010; 285(19):14585-93. DOI: 10.1074/jbc.M109.094334
Source: PubMed

ABSTRACT

Mammalian kidney development requires the functions of the Wilms tumor gene WT1 and the WNT/β-catenin signaling pathway. Recent studies have shown that WT1 negatively regulates WNT/β-catenin signaling, but the molecular mechanisms by which WT1 inhibits WNT/β-catenin signaling are not completely understood. In this study, we identified a gene, CXXC5, which we have renamed WID (WT1-induced Inhibitor of Dishevelled), as a novel WT1 transcriptional target that negatively regulates WNT/β-catenin signaling. WT1 activates WID transcription through the upstream enhancer region. In the developing kidney, Wid and Wt1 are coexpressed in podocytes of
maturing nephrons. Structure-function analysis demonstrated that WID interacts with Dishevelled via its C-terminal CXXC zinc finger and Dishevelled binding domains and potently inhibits WNT/β-catenin signaling in vitro and in vivo. WID is evolutionarily conserved, and ablation of wid in zebrafish embryos with antisense morpholino oligonucleotides perturbs embryonic kidney development. Taken together, our
results demonstrate that the WT1 negatively regulates WNT/β-catenin pathway via its target gene WID and further suggest a role for WID in nephrogenesis.

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    • "Wnt/β-catenin downstream signaling is also negatively regulated by the product of the recently identified WT1 target gene CXXC5 (syn. WID), which interacts with the immediate downstream effector of the frizzled receptor, Disheveled (Kim et al., 2010). The local oxygen environment controls the Notch pathway and the expression of TGF-β (Scheid et al., 2002; Schäffer et al., 2003; Chen et al., 2007; Sahlgren et al., 2008; Zheng et al., 2008), which is also regulated by WT1 (Dey et al., 1994; Jin et al., 1999). "
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    • "Thus, PAWR compromises the WNT signalling pathway, which may explain some of the findings by Wang et al (2008). CXXC5 (also upregulated by MLL-AFF1) encodes the 'WT1-induced Inhibitor of Dishevelled' (WID; Kim et al, 2010). WID directly binds to the Dishevelled protein and abrogates WNT signalling, thus simulating the absence of FRIZZLED ligands. "
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