WT1 in disease: shifting the epithelial–mesenchymal balance

Abstract

WT1 is a versatile gene that controls transitions between the mesenchymal and epithelial state of cells in a tissue-context dependent manner. As such, WT1 is indispensable for normal development of many organs and tissues. Uncontrolled epithelial to mesenchymal transition (EMT) is a hallmark of a diverse array of pathologies and disturbance of mesenchymal to epithelial transition (MET) has been associated with a number of developmental abnormalities. It is therefore not surprising that WT1 has been linked to many of these. Here we review the role of WT1 in proper control of the mesenchymal-epithelial balance of cells and discuss how far these roles can explain the role of WT1 in a variety of disease states.

Adiponectin Promotes Functional Recovery after Podocyte Ablation

“…Ablation of podocytes did not significantly alter POD-KO serum glucose levels (Supplemental Figure 5). Tubule epithelial cells were also positive for WT1 in late-stage POD-KO sections (Supplemental Figure 5), suggesting cell differentiation 27 and further deviation from normalcy. Adiponectin null POD-KO mice demonstrated reduced ClCr (F [4,20]=2.076, P=0.1220; Figure 4C).…”

“…POD-KO mice also exhibited tubule epithelial cell WT1 labeling after dimerization, similar to a previous report linking differentiation with altered renal function. 27 Reduced adiponectin levels in obesity would probably limit the potential for patient recovery in FSGS. Weight loss increases adiponectin levels and has demonstrated the ability to reduce obesity-related FSGS; our findings further reinforce the utility of this prescribed lifestyle change for obese patients.…”

“…In contrast to the POD-KO mice, PODTg mice maintained normal ClCr ( Figure 4C). Despite a similar percentage of podocytes lost at day 7, POD-Tg mice exhibited heightened albuminuria ( Figure 4D) compared with POD mice (F [4,27]=3.473, P=0.02). Adiponectin-overexpressing POD-Tg mice did, however, quickly recover, with restoration of WT1 and podoplanin expression, and presented less albumin excretion by 28 days, despite their early heightened peak levels ( Figure 4D and Supplemental Figure 1).…”

Transcriptional Regulation by the Wilms Tumor Protein, Wt1, Suggests a Role of the Metalloproteinase Adamts16 in Murine Genitourinary Development

“…4A). Wt1 belongs to the Cys 2 -His 2 class of zinc finger proteins and promotes mesenchymal-to-epithelial transition during the early stages of kidney development (35,45). Kidney formation in Wt1-deficient mouse embryos, which are commonly lethal by 13.5 d.p.c., was disrupted due to apoptosis of the metanephric mesenchyme and a failure of ureteric bud branching (35).…”

Wilms Tumor Suppressor, WT1, Suppresses Epigenetic Silencing of the β-Catenin Gene

“…ϪKTS isoforms exert transcriptional inhibition of target genes by binding to conserved motifs in their promoter regions (16). To ascertain whether WT1B binds the promoter region of EZH2 specifically, we performed ChIP followed by quantitative PCR for the 1-kb 5Ј-flanking region and an intronic region between exon 1 and exon 2 of EZH2 in amMSC WT1B .…”