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

Myoung Shin Kim1, Seung Kew Yoon, Frank Bollig

  • 1Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.

The Journal of Biological Chemistry
|March 12, 2010
PubMed

Insights

The Wilms tumor gene WT1 inhibits kidney development pathways by activating WID. This WT1-induced Inhibitor of Dishevelled (WID) protein then blocks WNT/beta-catenin signaling, crucial for nephrogenesis.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • Mammalian kidney development relies on Wilms tumor gene WT1 and WNT/beta-catenin signaling.
  • WT1 is known to negatively regulate WNT/beta-catenin signaling, but the precise mechanisms remain unclear.

Purpose of the Study:

  • To identify novel WT1 target genes involved in regulating WNT/beta-catenin signaling.
  • To elucidate the molecular mechanisms by which WT1 inhibits this pathway during kidney development.

Main Methods:

  • Gene identification and renaming (CXXC5 to WID).
  • Analysis of WT1 binding to the WID enhancer region.
  • Structure-function studies of WID protein interaction with Dishevelled.
  • In vitro and in vivo inhibition assays of WNT/beta-catenin signaling.
  • Zebrafish embryo studies using antisense morpholino oligonucleotides to ablate WID.

Main Results:

  • CXXC5, renamed WID (WT1-induced Inhibitor of Dishevelled), was identified as a novel WT1 transcriptional target.
  • WT1 activates WID transcription via an upstream enhancer.
  • WID interacts with Dishevelled (Dvl) and inhibits WNT/beta-catenin signaling both in vitro and in vivo.
  • WID is evolutionarily conserved.
  • Ablation of WID in zebrafish embryos disrupted kidney development.

Conclusions:

  • WT1 negatively regulates the WNT/beta-catenin pathway through its target gene, WID.
  • WID plays a significant role in mammalian nephrogenesis.
  • This study reveals a new regulatory axis in kidney development involving WT1, WID, and WNT/beta-catenin signaling.

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