A novel Wilms Tumor 1 (WT1) target gene negatively regulates the WNT signaling pathway

MS Kim, SK Yoon, F Bollig, J Kitagaki, W Hur, NJ Whye, YP Wu, MN Rivera, JY Park, HS Kim, K Malik, DW Bell, C Englert, AO Perantoni, SB Lee

Research output: Contribution to journalArticle (Academic Journal)peer-review

68 Citations (Scopus)

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.
Translated title of the contributionA novel Wilms Tumor 1 (WT1) target gene negatively regulates the WNT signaling pathway
Original languageEnglish
Pages (from-to)14585 - 14593
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number19
DOIs
Publication statusPublished - 7 May 2010

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