Disease relevance of Wt1

• The Wilms' tumor suppressor gene, Wt1, is required for mesenchymal cells to complete this developmental program [1].
• Taken together, our findings demonstrate a continuous requirement for Wt1 in normal retina formation with a critical role in Pou4f2-dependent ganglion cell differentiation [2].
• To help elucidate this, we generated a mouse strain carrying the missense mutation Wt1 R394W, which predisposes humans to glomerulosclerosis and early-onset renal failure (Denys-Drash syndrome [DDS]) [3].
• Using an inducible U2OS osteosarcoma cell line, it is shown that upon Wt1 induction, endogenous nephrin mRNA becomes highly upregulated [4].
• This was, at least in part, due to irradiation and not Wt1 heterozygosity because wild-type recipients also developed albuminuria within 24 weeks of BMT with 1,000 cGy [5].

High impact information on Wt1

• Alternative splicing of Wt1 results in the insertion or omission of the three amino acids KTS between zinc fingers 3 and 4 [6].
• Activation of Wt1 in an inducible cell line significantly enhanced TrkB expression [7].
• We report here expression of the Wilms' tumor gene-1, Wt1, in coronary vessels, which could contribute to the defective cardiac vascularization in Wt1-/- mice [7].
• These findings demonstrate that transcriptional activation of the TrkB neurotrophin receptor gene by the Wilms' tumor suppressor Wt1 is a crucial mechanism for normal vascularization of the developing heart [7].
• Furthermore, the high-affinity neurotrophin receptor TrkB, which is expressed in the epicardium and subepicardial blood vessels, was nearly absent from Wt1-deficient hearts [7].

Chemical compound and disease context of Wt1

• Renal mesenchyme from control embryos expressed Wilms' tumor 1 (Wt1), but this transcription factor, which is indispensable for kidney development, failed to express in metanephroi of retinoic acid-exposed embryos [8].
• This study analyzed a potential regulation of nephrin by the Wilms' tumor protein, Wt1 [4].
• Wt1 expression in the coronary vessels of the ischemic heart was mimicked by exposure of rats to normobaric hypoxia (8% O2) and 0.1% CO, respectively [9].

Biological context of Wt1

• Transgenic experiments revealed that the identified Wt1 consensus motif in the NTRK2 promoter was necessary to direct expression of a reporter gene to the epicardium and the developing vasculature of embryonic mouse hearts [7].
• Forced expression of Wt1 in cultured cells causes an up-regulation of Pou4f2 mRNA [2].
• Wt1-/- mice confirm that Wt1 is essential for the inception of kidney development; cells that ought to form kidneys die by apoptosis instead [10].
• In the rare XX<-->XY DDS males the Sertoli cell lineage was largely derived from Wt1 mutant XY cells [11].
• This mouse presents a mutation in chromosome 2 which affects the gene Pax6 and other nearby genes, such as the Wt1 gene and the gene of the Reticulocalbin [12].

Anatomical context of Wt1

• By contrast, Wt1 and Sf1, which are expressed prior to Sry and necessary for gonad development in both sexes, were expressed normally in both types of mutant XY gonads [13].
• Here, we demonstrate that several markers, including Pax-2, Six-2, and GDNF, were present as RNAs in the metanephric mesenchyme of Wt1 -/- embryos [1].
• However, the Wolffian duct from Wt1 -/- embryos was a competent inducer of wild-type metanephric mesenchyme [1].
• Wt1 mutant cells colonized glomeruli efficiently, including podocytes, but some sclerotic glomeruli contained no detectable Wt1 mutant cells [14].
• Wt1 is expressed in a rich pattern during renal development suggesting that it acts at three stages: determination of the kidney area, the differentiation of nephrons and maturation of glomeruli [10].

Associations of Wt1 with chemical compounds

• There is, however, no genetic evidence for a function during nephron differentiation because this stage is never reached in Wt1-/- mice [10].
• Finally, treatment of mice with an angiotensin-converting enzyme (ACE) inhibitor normalized renal function and induced upregulation of the important structural molecule nephrin via a Wt1-independent pathway [15].
• Wt1 expression and organogenesis were both restored, however, when metanephroi from retinoic acid-treated pregnancies were grown in serum-containing media [8].

Physical interactions of Wt1

• Stimulation of the Pou4f2 promoter required a Wt1 binding element that was similar to a degenerative consensus site previously identified in other Wt1 responsive genes [16].

Regulatory relationships of Wt1

• These results strongly indicate that Wt1 might be under the control of Sry during gonadal differentiation in the mouse [17].
• Transient co-transfection of a Wt1 expression construct activated a Pou4f2 promoter-reporter construct approximately 4-fold [16].

Other interactions of Wt1

• In these triple mutants, the metanephric blastema condenses, and expression of early patterning genes, Pax2 and Wt1, is unperturbed [18].
• Our data suggest a pathway in which the products of the Wt1 and Lhx9 genes activate expression of Sf1 and thus mediate early gonadogenesis [19].
• Coronary vessel development requires activation of the TrkB neurotrophin receptor by the Wilms' tumor transcription factor Wt1 [7].
• Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1 [15].
• In conclusion, we identified Pou4f2 as a novel downstream target gene of Wt1 [16].

Analytical, diagnostic and therapeutic context of Wt1

• To determine whether WT1 functions other than to induce expression of factors that stimulate ureteric bud outgrowth, Wt1 -/- metanephric mesenchymes were recombined with wild-type ureteric buds in organ culture, but this failed to rescue tubulogenesis [1].
• The critical DNA-binding site for activation of the NTRK2 promoter by Wt1 was delineated by DNase I footprint analysis and electrophoretic mobility shift assay [7].
• In the present study, the fate of Wt1 mutant cells in chimeric kidneys was assessed by in situ marker analysis, and immunocytochemistry was used to re-examine the claim that glomerulosclerosis (GS) is caused by loss of WT1 and persistent Pax-2 expression by podocytes [14].
• In conclusion, transplantation of wild-type BM attenuates progression of mesangial sclerosis in the Wt1+/- model of renal disease, and the mechanism by which this occurs may involve engraftment of BM-derived cells in the renal parenchyma [5].

References