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

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Mar 12

PMID 20220130

Citations 55

Authors

Myoung Shin Kim

Seung Kew Yoon

Frank Bollig

Jirouta Kitagaki

Wonhee Hur

Nathan J Whye

Yun-Ping Wu

Miguel N Rivera

Jik Young Park

Ho-Shik Kim

Karim Malik

Daphne W Bell

Christoph Englert

Alan O Perantoni

Sean Bong Lee

Affiliations

Soon will be listed here.

Abstract

Mammalian kidney development requires the functions of the Wilms tumor gene WT1 and the WNT/beta-catenin signaling pathway. Recent studies have shown that WT1 negatively regulates WNT/beta-catenin signaling, but the molecular mechanisms by which WT1 inhibits WNT/beta-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/beta-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/beta-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/beta-catenin pathway via its target gene WID and further suggest a role for WID in nephrogenesis.

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