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


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.

Download full-text


Available from: Sean Bong Lee, Jan 22, 2014
35 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adequate tissue oxygenation is a prerequisite for normal development of the embryo. Most fetal organs are exquisitely susceptible to hypoxia which occurs when the delivery of oxygen is exceeded by the actual demand. Developmental abnormalities due to insufficient supply with oxygen can result from the impaired expression of genes with essential functions during embryogenesis. As such, the Wilms' tumor gene, WT1, is among the fetal genes that are regulated by the local oxygen tension. WT1 was originally discovered as a tumor suppressor gene owing to loss-of-function mutations in a subset of pediatric renal neoplasias, known as nephroblastomas or Wilms' tumors. Wilms' tumors can arise when pluripotent progenitor cells in the embryonic kidney continue to proliferate rather than differentiating to glomeruli and tubules. WT1 encodes a zinc finger protein, of which multiple isoforms exist due to alternative mRNA splicing in addition to translational and post-translational modifications. While some WT1 isoforms function as transcription factors, other WT1 proteins are presumably involved in post-transcriptional mRNA processing. However, the role of WT1 reaches far beyond that of a tumor suppressor as homozygous disruption of Wt1 in mice caused embryonic lethality with a failure of normal development of the kidneys, gonads, heart, and other tissues. WT1 mutations in humans are associated with malformation of the genitourinary system. A common paradigm of WT1 expressing cells is their capacity to switch between a mesenchymal and epithelial state. Thus, WT1 likely acts as a master switch that enables cells to undergo reciprocal epithelial-to-mesenchymal transition. Impairment of renal precursor cells to differentiate along the epithelial lineage due to WT1 mutations may favor malignant tumor growth. This article shall provide a concise review of the function of WT1 in development and disease with special consideration of its regulation by molecular oxygen.
    Frontiers in Molecular Neuroscience 02/2011; 4:4. DOI:10.3389/fnmol.2011.00004 · 4.08 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Infant acute leukaemia is characterised by specific genetic rearrangements and a rapid onset of disease shortly after birth. The vast majority of these cases bear rearranged MLL alleles. However, many facets of MLL-rearranged leukaemia are largely unknown. Basically, there exists a fundamental and evolutionary conserved relationship between the family of MLL/Trithorax proteins and the regulation of HOX gene clusters. Therefore, direct MLL fusion proteins are per se able to deregulate HOX genes, except when reciprocal MLL fusion proteins come into play. This reviews discusses (i) the current situation in MLL-rearranged leukaemia, (ii) the molecular and genetic tools to functionally investigate the many different MLL fusions, (iii) the latency of disease development, (iv) a novel cancer mechanism that has been recently uncovered when different MLL fusion protein complexes were characterized, (v) mutated signalling pathways in MLL-rearranged leukaemia and (vi) presents new ideas on how a given MLL fusion protein may modulate existing signalling pathways in leukaemic cells. The hypothesis is posed that the many different fusion partners of MLL are critically distinct entities for which specific inhibitors should be identified in the future.
    British Journal of Haematology 01/2011; 152(2):141-54. DOI:10.1111/j.1365-2141.2010.08459.x · 4.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Kidney development has been studied over the past sixty years as a model of embryonic induction during organogenesis. Wilms' tumor-1 (WT1), that encodes a transcription factor and RNA-binding protein, was one of the first tumor suppressor genes identified, and was soon thereafter shown to be associated with syndromic forms of childhood kidney disease and gonadal dysgenesis. Kidney agenesis, resulting from a null mutation in the WT1 gene, was one of the first examples of organ agenesis resulting from a gene targeting experiment. Thus, the study of the WT1 gene and its encoded proteins has been at the forefront of developmental biology, tumor biology and the molecular basis for disease. WT1 is now known to have an important role in kidney progenitor cells during development. This review will discuss recent advances in our understanding of kidney progenitor cells, and the recent identification of WT1 target genes in these cells.
    Organogenesis 04/2010; 6(2):61-70. DOI:10.4161/org.6.2.11928 · 2.80 Impact Factor
Show more