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Wt1  -  Wilms tumor 1 homolog

Mus musculus

Synonyms: D630046I19Rik, Wilms tumor protein homolog, Wt-1
 
 
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Disease relevance of Wt1

 

High impact information on Wt1

 

Chemical compound and disease context of Wt1

 

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

  1. Initial differentiation of the metanephric mesenchyme is independent of WT1 and the ureteric bud. Donovan, M.J., Natoli, T.A., Sainio, K., Amstutz, A., Jaenisch, R., Sariola, H., Kreidberg, J.A. Dev. Genet. (1999) [Pubmed]
  2. The Wilms' tumor gene Wt1 is required for normal development of the retina. Wagner, K.D., Wagner, N., Vidal, V.P., Schley, G., Wilhelm, D., Schedl, A., Englert, C., Scholz, H. EMBO J. (2002) [Pubmed]
  3. The Wt1+/R394W mouse displays glomerulosclerosis and early-onset renal failure characteristic of human Denys-Drash syndrome. Gao, F., Maiti, S., Sun, G., Ordonez, N.G., Udtha, M., Deng, J.M., Behringer, R.R., Huff, V. Mol. Cell. Biol. (2004) [Pubmed]
  4. The major podocyte protein nephrin is transcriptionally activated by the Wilms' tumor suppressor WT1. Wagner, N., Wagner, K.D., Xing, Y., Scholz, H., Schedl, A. J. Am. Soc. Nephrol. (2004) [Pubmed]
  5. Bone marrow transplantation can attenuate the progression of mesangial sclerosis. Guo, J.K., Schedl, A., Krause, D.S. Stem Cells (2006) [Pubmed]
  6. Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation. Hammes, A., Guo, J.K., Lutsch, G., Leheste, J.R., Landrock, D., Ziegler, U., Gubler, M.C., Schedl, A. Cell (2001) [Pubmed]
  7. Coronary vessel development requires activation of the TrkB neurotrophin receptor by the Wilms' tumor transcription factor Wt1. Wagner, N., Wagner, K.D., Theres, H., Englert, C., Schedl, A., Scholz, H. Genes Dev. (2005) [Pubmed]
  8. Implication of Wt1 in the pathogenesis of nephrogenic failure in a mouse model of retinoic acid-induced caudal regression syndrome. Tse, H.K., Leung, M.B., Woolf, A.S., Menke, A.L., Hastie, N.D., Gosling, J.A., Pang, C.P., Shum, A.S. Am. J. Pathol. (2005) [Pubmed]
  9. The Wilms' tumor suppressor Wt1 is expressed in the coronary vasculature after myocardial infarction. Wagner, K.D., Wagner, N., Bondke, A., Nafz, B., Flemming, B., Theres, H., Scholz, H. FASEB J. (2002) [Pubmed]
  10. Development of an siRNA-based method for repressing specific genes in renal organ culture and its use to show that the Wt1 tumour suppressor is required for nephron differentiation. Davies, J.A., Ladomery, M., Hohenstein, P., Michael, L., Shafe, A., Spraggon, L., Hastie, N. Hum. Mol. Genet. (2004) [Pubmed]
  11. Gonadal effects of a mouse Denys-Drash syndrome mutation. Patek, C.E., Saunders, P.T., Miles, C.G., Berry, R.L., Hastie, N.D., Sharpe, R.M., Hooper, M.L. Transgenic Res. (2005) [Pubmed]
  12. Modifications of the retina neuronal populations of the heterozygous mutant small eye mouse, the Sey(Dey). Curto, G.G., Lara, J.M., Parrilla, M., Aij??n, J., Velasco, A. Brain Res. (2007) [Pubmed]
  13. Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2. Tevosian, S.G., Albrecht, K.H., Crispino, J.D., Fujiwara, Y., Eicher, E.M., Orkin, S.H. Development (2002) [Pubmed]
  14. Murine Denys-Drash syndrome: evidence of podocyte de-differentiation and systemic mediation of glomerulosclerosis. Patek, C.E., Fleming, S., Miles, C.G., Bellamy, C.O., Ladomery, M., Spraggon, L., Mullins, J., Hastie, N.D., Hooper, M.L. Hum. Mol. Genet. (2003) [Pubmed]
  15. An inducible mouse model for PAX2-dependent glomerular disease: insights into a complex pathogenesis. Wagner, K.D., Wagner, N., Guo, J.K., Elger, M., Dallman, M.J., Bugeon, L., Schedl, A. Curr. Biol. (2006) [Pubmed]
  16. The Wilms' tumor suppressor Wt1 encodes a transcriptional activator of the class IV POU-domain factor Pou4f2 (Brn-3b). Wagner, K.D., Wagner, N., Schley, G., Theres, H., Scholz, H. Gene (2003) [Pubmed]
  17. Down-regulation of endogenous Wt1 expression by Sry transgene in the murine embryonic mesonephros-derived M15 cell line. Ito, M., Miyagishi, M., Murata, C., Kawasaki, H., Baba, T., Tachi, C., Taira, K. J. Reprod. Dev. (2006) [Pubmed]
  18. Hox11 paralogous genes are essential for metanephric kidney induction. Wellik, D.M., Hawkes, P.J., Capecchi, M.R. Genes Dev. (2002) [Pubmed]
  19. The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1. Wilhelm, D., Englert, C. Genes Dev. (2002) [Pubmed]
 
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