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Gene Review

Wnt4  -  wingless-type MMTV integration site family...

Mus musculus

Synonyms: Protein Wnt-4, Wnt-4
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Disease relevance of Wnt4

  • The level of expression of Wnt2 and Wnt4 was 10- to 20-fold higher in fibroadenomas than it was in normal or malignant breast tissue, and in 10% of tumors Wnt7b expression was 30-fold higher than in normal or benign breast tissues [1].
  • Similar to the cell lines, the level of Wnt4 mRNA expression was significantly higher in the normal endometrium than endometrial carcinoma [2].
  • These findings suggest that Wnt-4 stimulates Nppc in a TCF/LEF-dependent manner after renal injury and thus may contribute to limiting renal fibrosis [3].
  • Wnt4 expression is induced throughout the collecting ducts in four murine models of renal injury that produce tubulointerstitial fibrosis: folic acid-induced nephropathy, unilateral ureteral obstruction, renal needle puncture, and genetic polycystic kidney disease [4].
  • The cells were smaller and grew to a higher density than cells containing a control retrovirus or cells expressing Wnt-4 or Wnt-5b [5].

High impact information on Wnt4


Biological context of Wnt4

  • These results were supported by in vivo observations using Wnt4 gene-disrupted mice, in which Dax-1 gene expression was decreased significantly in sexually differentiating female gonads [8].
  • Using these mutant mice, we sought to determine the importance of Msx-1 (another homeobox gene formerly known as Hox-7.1) and of Wnt4 (a ligand of the Wnt family) signaling in implantation because of their reported functions during development [9].
  • Lack of Wnt4 gives rise to masculinization of the XX gonad and we showed previously that the role of WNT4 was to inhibit endothelial and steroidogenic cell migration into the developing ovary [10].
  • Wnt4 is required for proper male as well as female sexual development [10].
  • The data indicate that all Wnt genes were expressed in vitro, six out of seven Wnt genes (Wnt 2, 3, 4, 5a, 7a and 7b) were expressed endogenously in the human endometrium, their mRNA expression was hormonally independent and Wnt4 gene down-regulation as well as down-regulation of Wnt 2, 3 and 5a may be associated with endometrial carcinoma [2].

Anatomical context of Wnt4

  • XY(Sry-)Ods/+ males also failed to establish the correct male-specific pattern of vascularization at the time of sex determination, which could be correlated to an inability of XY(Sry-),Ods/+ males to fully down-regulate Wnt4 expression in the embryonic gonad [11].
  • Wnt4 is required for Müllerian duct initiation, whereas Wnt7a is required for subsequent differentiation [12].
  • 5. Wnt11 is highly expressed at the gastro-esophageal junctions, while Wnt4 is found in the epithelium lining the pyloric region of the stomach but not in the epithelium of the prospective gland region [13].
  • Analysis of resulting Sox9(-/-) XY gonads up to E15.5 reveals immediate, complete sex reversal, as shown by expression of the early ovary-specific markers Wnt4 and Foxl2 and by lack of testis cord and Leydig cell formation [14].
  • The expression of Wnt5a is confined to the mesenchymal compartment, while expression of Wnt4 is found both in the intestinal epithelium and the mesenteric anlage [13].

Associations of Wnt4 with chemical compounds

  • In the absence of FGF8 signaling, nephron formation is initiated, but the nascent nephrons do not express Wnt4 or Lim1, and nephrogenesis does not progress to the S-shaped body stage [15].
  • Here we demonstrate that Wnt-4, a secreted glycoprotein which is required for tubule formation, is sufficient to trigger tubulogenesis in isolated metanephric mesenchyme, whereas Wnt-11 which is expressed in the tip of the growing ureter is not [16].
  • Consistent with these in vivo data, Wnt4 repressed steroidogenesis in adrenocortical and Leydig cell lines, as evidenced by reduced progesterone secretion and 3beta-hydroxysteroid dehydrogenase activity [17].
  • Doxycycline induction of WT1-A or WT1-D expression in HEK293 stable transfectants also elicited an elevation in Wnt4 expression [18].
  • PR and Wnt-4 mRNAs colocalize to the luminal compartment of the ductal epithelium [19].

Physical interactions of Wnt4

  • Our results in combination with work from Xenopus laevis (not shown) lead us to believe that Wnt-4 binds both canonical and noncanonical Frizzled receptors, thereby activating Wnt signaling pathways that may each contribute to kidney tubulogenesis [20].

Regulatory relationships of Wnt4

  • These data indicate that activation of SOX9 in the gonad is sufficient to trigger all the downstream events needed for the development of a fully fertile male and provide evidence that Sox9 may down-regulate Wnt4 expression in the gonad [11].
  • Later, at the bud stage, epithelial Wnt4 and Tgfbeta1 regulate Sema3a expression in the dental mesenchyme [21].
  • In addition, Wnt4 stimulates mesenchymal expression of Msx1 transcription factor, which is essential for tooth formation, and Tgfbeta1 proliferation of the dental mesenchymal cells [21].
  • The modified growth pattern induced by Wnt-4 expression was similar to that induced by Wnt-1, one of the members of the Wnt gene family activated by mouse mammary tumour virus [22].
  • In support of a functional role for Wnt-4 in these activated myofibroblasts, Wnt-4 induces stabilization of cytosolic beta-catenin in a cultured myofibroblast cell line [4].
  • Accordingly, knockdown of endogenous MTA3 stimulates Wnt4 expression and Wnt cellular targets [23].

Other interactions of Wnt4

  • p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation [24].
  • This interaction may be established by signals mediated by Wnt1 and Wnt4, leading to increased Tcf-dependent transcriptional activity in thymocytes, as demonstrated in Tcf-LacZ reporter mice [25].
  • Induction of Nppc occurred in identical cell populations to those in which Wnt4 is induced after renal injury [3].
  • Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads [26].
  • We thus conclude that Wnt4 signaling mediates the increased expression of Dax-1 as the ovary becomes sexually differentiated [8].

Analytical, diagnostic and therapeutic context of Wnt4


  1. Differential expression of human Wnt genes 2, 3, 4, and 7B in human breast cell lines and normal and disease states of human breast tissue. Huguet, E.L., McMahon, J.A., McMahon, A.P., Bicknell, R., Harris, A.L. Cancer Res. (1994) [Pubmed]
  2. Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma. Bui, T.D., Zhang, L., Rees, M.C., Bicknell, R., Harris, A.L. Br. J. Cancer (1997) [Pubmed]
  3. CNP gene expression is activated by Wnt signaling and correlates with Wnt4 expression during renal injury. Surendran, K., Simon, T.C. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  4. A role for Wnt-4 in renal fibrosis. Surendran, K., McCaul, S.P., Simon, T.C. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  5. Alterations of the growth characteristics of the fibroblast cell line C3H 10T1/2 by members of the Wnt gene family. Bradbury, J.M., Niemeyer, C.C., Dale, T.C., Edwards, P.A. Oncogene (1994) [Pubmed]
  6. Mesenchymal to epithelial conversion in rat metanephros is induced by LIF. Barasch, J., Yang, J., Ware, C.B., Taga, T., Yoshida, K., Erdjument-Bromage, H., Tempst, P., Parravicini, E., Malach, S., Aranoff, T., Oliver, J.A. Cell (1999) [Pubmed]
  7. Female development in mammals is regulated by Wnt-4 signalling. Vainio, S., Heikkilä, M., Kispert, A., Chin, N., McMahon, A.P. Nature (1999) [Pubmed]
  8. Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1) gene transcription is regulated by wnt4 in the female developing gonad. Mizusaki, H., Kawabe, K., Mukai, T., Ariyoshi, E., Kasahara, M., Yoshioka, H., Swain, A., Morohashi, K. Mol. Endocrinol. (2003) [Pubmed]
  9. Uterine Msx-1 and Wnt4 signaling becomes aberrant in mice with the loss of leukemia inhibitory factor or Hoxa-10: evidence for a novel cytokine-homeobox-Wnt signaling in implantation. Daikoku, T., Song, H., Guo, Y., Riesewijk, A., Mosselman, S., Das, S.K., Dey, S.K. Mol. Endocrinol. (2004) [Pubmed]
  10. Wnt4 is required for proper male as well as female sexual development. Jeays-Ward, K., Dandonneau, M., Swain, A. Dev. Biol. (2004) [Pubmed]
  11. Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry. Qin, Y., Bishop, C.E. Hum. Mol. Genet. (2005) [Pubmed]
  12. Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus. Mericskay, M., Kitajewski, J., Sassoon, D. Development (2004) [Pubmed]
  13. Expression patterns of Wnt genes in mouse gut development. Lickert, H., Kispert, A., Kutsch, S., Kemler, R. Mech. Dev. (2001) [Pubmed]
  14. Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Barrionuevo, F., Bagheri-Fam, S., Klattig, J., Kist, R., Taketo, M.M., Englert, C., Scherer, G. Biol. Reprod. (2006) [Pubmed]
  15. FGF8 is required for cell survival at distinct stages of nephrogenesis and for regulation of gene expression in nascent nephrons. Grieshammer, U., Cebrián, C., Ilagan, R., Meyers, E., Herzlinger, D., Martin, G.R. Development (2005) [Pubmed]
  16. Wnt-4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney. Kispert, A., Vainio, S., McMahon, A.P. Development (1998) [Pubmed]
  17. Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta-catenin synergy. Jordan, B.K., Shen, J.H., Olaso, R., Ingraham, H.A., Vilain, E. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  18. Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1. Sim, E.U., Smith, A., Szilagi, E., Rae, F., Ioannou, P., Lindsay, M.H., Little, M.H. Oncogene (2002) [Pubmed]
  19. Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Brisken, C., Heineman, A., Chavarria, T., Elenbaas, B., Tan, J., Dey, S.K., McMahon, J.A., McMahon, A.P., Weinberg, R.A. Genes Dev. (2000) [Pubmed]
  20. Wnt-4 activates the canonical beta-catenin-mediated Wnt pathway and binds Frizzled-6 CRD: functional implications of Wnt/beta-catenin activity in kidney epithelial cells. Lyons, J.P., Mueller, U.W., Ji, H., Everett, C., Fang, X., Hsieh, J.C., Barth, A.M., McCrea, P.D. Exp. Cell Res. (2004) [Pubmed]
  21. Coordination of trigeminal axon navigation and patterning with tooth organ formation: epithelial-mesenchymal interactions, and epithelial Wnt4 and Tgfbeta1 regulate semaphorin 3a expression in the dental mesenchyme. Kettunen, P., Løes, S., Furmanek, T., Fjeld, K., Kvinnsland, I.H., Behar, O., Yagi, T., Fujisawa, H., Vainio, S., Taniguchi, M., Luukko, K. Development (2005) [Pubmed]
  22. Wnt-4 expression induces a pregnancy-like growth pattern in reconstituted mammary glands in virgin mice. Bradbury, J.M., Edwards, P.A., Niemeyer, C.C., Dale, T.C. Dev. Biol. (1995) [Pubmed]
  23. Metastatic tumor antigen 3 is a direct corepressor of the Wnt4 pathway. Zhang, H., Singh, R.R., Talukder, A.H., Kumar, R. Genes Dev. (2006) [Pubmed]
  24. p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Devgan, V., Mammucari, C., Millar, S.E., Brisken, C., Dotto, G.P. Genes Dev. (2005) [Pubmed]
  25. Wnt signaling is required for thymocyte development and activates Tcf-1 mediated transcription. Staal, F.J., Meeldijk, J., Moerer, P., Jay, P., van de Weerdt, B.C., Vainio, S., Nolan, G.P., Clevers, H. Eur. J. Immunol. (2001) [Pubmed]
  26. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. Kim, Y., Kobayashi, A., Sekido, R., DiNapoli, L., Brennan, J., Chaboissier, M.C., Poulat, F., Behringer, R.R., Lovell-Badge, R., Capel, B. PLoS Biol. (2006) [Pubmed]
  27. Matrilysin (MMP-7) expression in renal tubular damage: association with Wnt4. Surendran, K., Simon, T.C., Liapis, H., McGuire, J.K. Kidney Int. (2004) [Pubmed]
  28. Wnt4 expression in the differentiating gonad of the frog Rana rugosa. Oshima, Y., Hayashi, T., Tokunaga, S., Nakamura, M. Zool. Sci. (2005) [Pubmed]
  29. A microarray analysis of the XX Wnt4 mutant gonad targeted at the identification of genes involved in testis vascular differentiation. Coveney, D., Ross, A.J., Slone, J.D., Capel, B. Gene Expr. Patterns (2007) [Pubmed]
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