Gene Symbol: Wnt4
Description: Wnt family member 4
Alias: protein Wnt-4, wingless-related MMTV integration site 4, wingless-type MMTV integration site family, member 4
Species: rat
Products:     Wnt4

Top Publications

  1. Brisken C, Heineman A, Chavarria T, Elenbaas B, Tan J, Dey S, et al. Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev. 2000;14:650-4 pubmed
    ..Progesterone induces Wnt-4 in mammary epithelial cells and is required for increased Wnt-4 expression during pregnancy. Thus, Wnt signaling is essential in mediating progesterone function during mammary gland morphogenesis. ..
  2. De Menna M, D Amato V, Ferraro A, Fusco A, Di Lauro R, Garbi C, et al. Wnt4 inhibits cell motility induced by oncogenic Ras. Oncogene. 2013;32:4110-9 pubmed publisher
    ..By using a model of malignant transformation induced by Ras, we identified Wnt4 as an early target of Ras oncogenic signaling...
  3. Lyons J, Mueller U, Ji H, Everett C, Fang X, Hsieh J, et al. 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. Exp Cell Res. 2004;298:369-87 pubmed
  4. Vainio S, Heikkilä M, Kispert A, Chin N, McMahon A. Female development in mammals is regulated by Wnt-4 signalling. Nature. 1999;397:405-9 pubmed
    ..Wnt-4 may also be required for maintenance of the female germ line. Thus, the establishment of sexual dimorphism is under the control of both local and systemic signals. ..
  5. Stark K, Vainio S, Vassileva G, McMahon A. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature. 1994;372:679-83 pubmed
    ..Thus, Wnt-4 appears to act as an autoinducer of the mesenchyme to epithelial transition that underlies nephron development. ..
  6. Jordan B, Mohammed M, Ching S, Delot E, Chen X, Dewing P, et al. Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans. Am J Hum Genet. 2001;68:1102-9 pubmed
    ..These observations suggest that mammalian sex determination is sensitive to dosage, at multiple steps in its pathway. ..
  7. Jeays Ward K, Dandonneau M, Swain A. Wnt4 is required for proper male as well as female sexual development. Dev Biol. 2004;276:431-40 pubmed
    ..The signaling molecule WNT4 has been shown to be important in female sexual development...
  8. Heikkilä M, Peltoketo H, Leppäluoto J, Ilves M, Vuolteenaho O, Vainio S. Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology. 2002;143:4358-65 pubmed
    ..In summary, these results point to a role for Wnt-4 in adrenal gland development and function. ..
  9. Katayama S, Ashizawa K, Fukuhara T, Hiroyasu M, Tsuzuki Y, Tatemoto H, et al. Differential expression patterns of Wnt and beta-catenin/TCF target genes in the uterus of immature female rats exposed to 17alpha-ethynyl estradiol. Toxicol Sci. 2006;91:419-30 pubmed
    ..Although the time courses of Wnt4, Wnt5a, and Wnt7a mRNA status varied until 12 h after EE administration, all of them were simultaneously ..

More Information


  1. Biason Lauber A, de Filippo G, Konrad D, Scarano G, Nazzaro A, Schoenle E. WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report. Hum Reprod. 2007;22:224-9 pubmed
    ..Loss-of-function mutations in the WNT4 gene appear to cause developmental abnormalities of sexual differentiation in women and mice...
  2. Wang L, Shao Y, Ballock R. Thyroid hormone interacts with the Wnt/beta-catenin signaling pathway in the terminal differentiation of growth plate chondrocytes. J Bone Miner Res. 2007;22:1988-95 pubmed
    ..These data suggest that thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulating canonical Wnt/beta-catenin signaling. ..
  3. Carroll T, Park J, Hayashi S, Majumdar A, McMahon A. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell. 2005;9:283-92 pubmed
    ..Wnt9b acts upstream of another Wnt, Wnt4, in this process, and our data implicate canonical Wnt signaling as one of the major pathways in the organization ..
  4. Philibert P, Biason Lauber A, Rouzier R, Pienkowski C, Paris F, Konrad D, et al. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study. J Clin Endocrinol Metab. 2008;93:895-900 pubmed publisher
    Müllerian duct development depends on gene and hormone interactions. Female Wnt4-knockout mice lack müllerian ducts and are virilized due to the inappropriate expression of the enzymes required for androgen production (normally ..
  5. Jordan B, Shen J, Olaso R, Ingraham H, Vilain E. Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta-catenin synergy. Proc Natl Acad Sci U S A. 2003;100:10866-71 pubmed
    Genetic studies in mice suggest that Wnt4 signaling antagonizes expression of male hormones and effectively blocks male development in the female embryo...
  6. Yao H, Matzuk M, Jorgez C, Menke D, Page D, Swain A, et al. Follistatin operates downstream of Wnt4 in mammalian ovary organogenesis. Dev Dyn. 2004;230:210-5 pubmed
    b>Wnt4(-/-) XX gonads display features normally associated with testis differentiation, suggesting that WNT4 actively represses elements of the male pathway during ovarian development...
  7. Taki M, Kamata N, Yokoyama K, Fujimoto R, Tsutsumi S, Nagayama M. Down-regulation of Wnt-4 and up-regulation of Wnt-5a expression by epithelial-mesenchymal transition in human squamous carcinoma cells. Cancer Sci. 2003;94:593-7 pubmed
    ..These results indicated that Wnt-4 and Wnt-5a are oppositely affected by EMT, and down-regulation of Wnt-4 and up-regulation of Wnt-5a are possible markers of the malignant phenotype of human SCC. ..
  8. Louis I, Heinonen K, Chagraoui J, Vainio S, Sauvageau G, Perreault C. The signaling protein Wnt4 enhances thymopoiesis and expands multipotent hematopoietic progenitors through beta-catenin-independent signaling. Immunity. 2008;29:57-67 pubmed publisher
    ..Using gain-of-function and loss-of-function models, we found that Wnt4 differentially affected diverse subsets of hematopoietic stem and progenitor cells...
  9. Burn S, Webb A, Berry R, Davies J, Ferrer Vaquer A, Hadjantonakis A, et al. Calcium/NFAT signalling promotes early nephrogenesis. Dev Biol. 2011;352:288-98 pubmed publisher
    ..A (CSA), an inhibitor of Calcium/NFAT signalling, decreases nephron formation--a phenotype similar to that in Wnt4(-/-) embryos...
  10. Lokmane L, Heliot C, Garcia Villalba P, Fabre M, Cereghini S. vHNF1 functions in distinct regulatory circuits to control ureteric bud branching and early nephrogenesis. Development. 2010;137:347-57 pubmed publisher
  11. Giles A, Madec F, Friedrichsen S, Featherstone K, Chambers T, Harper C, et al. Wnt signaling in estrogen-induced lactotroph proliferation. J Cell Sci. 2011;124:540-7 pubmed publisher
    ..Here, using microarray analysis, we show that estrogen treatment increased expression of Wnt4 mRNA in adult Fischer rat pituitary tissue...
  12. Shan J, Jokela T, Peltoketo H, Vainio S. Generation of an allele to inactivate Wnt4 gene function conditionally in the mouse. Genesis. 2009;47:782-8 pubmed publisher
    The Wnt family member Wnt4 is critical for the development of several organs, including the kidney, gonad, and adrenal, mammary, and pituitary glands. To study its potential postnatal functions, we generated a floxed Wnt4 allele...
  13. Lee C, Buttitta L, May N, Kispert A, Fan C. SHH-N upregulates Sfrp2 to mediate its competitive interaction with WNT1 and WNT4 in the somitic mesoderm. Development. 2000;127:109-18 pubmed
    ..We further show that SFRP2-expressing cells can reduce the dermomyotome-inducing activity of WNT1 and WNT4, but not that of WNT3a...
  14. Kobayashi A, Shawlot W, Kania A, Behringer R. Requirement of Lim1 for female reproductive tract development. Development. 2004;131:539-49 pubmed
    ..These studies demonstrate an essential role for Lim1 in female reproductive tract development...
  15. Peltoketo H, Allinen M, Vuosku J, Kujala S, Lundan T, Salminen A, et al. Characterization and expression of the human WNT4; lack of associated germline mutations in high--to moderate--risk breast and ovarian cancer. Cancer Lett. 2004;213:83-90 pubmed
    b>Wnt4 is needed for correct development of several tissues in the mouse, and WNT4 is found here to be expressed in a temporal manner in human embryonic tissues. In addition, WNT4 mRNA is seen in several adult tissues. The 1...
  16. Itäranta P, Chi L, Seppänen T, Niku M, Tuukkanen J, Peltoketo H, et al. Wnt-4 signaling is involved in the control of smooth muscle cell fate via Bmp-4 in the medullary stroma of the developing kidney. Dev Biol. 2006;293:473-83 pubmed
    ..Thus, besides being critical for regulating mesenchymal to epithelial transformation in the cortical region in nephrogenesis, Wnt-4 signaling regulates the fate of smooth muscle cells in the developing medullary region. ..
  17. Wang L, Shao Y, Ballock R. Carboxypeptidase Z (CPZ) links thyroid hormone and Wnt signaling pathways in growth plate chondrocytes. J Bone Miner Res. 2009;24:265-73 pubmed publisher
    ..These data indicate that thyroid hormone may regulate terminal differentiation of growth plate chondrocytes in part by modulating Wnt signaling pathways through the induction of CPZ and subsequent CPZ-enhanced activation of Wnt-4. ..
  18. Chen M, Hornsby P. Adenovirus-delivered DKK3/WNT4 and steroidogenesis in primary cultures of adrenocortical cells. Horm Metab Res. 2006;38:549-55 pubmed
    The Wnt family molecules Dickkopf-3 (DKK3) and WNT4 are present at higher concentrations in the zona glomerulosa than in the rest of the adrenal cortex...
  19. Itäranta P, Lin Y, Peräsaari J, Roël G, Destree O, Vainio S. Wnt-6 is expressed in the ureter bud and induces kidney tubule development in vitro. Genesis. 2002;32:259-68 pubmed
    ..Wnt-6 also induces a secondary axis in early Xenopus embryos. We conclude that Wnt-6 is a candidate for the ureter epithelium-derived signal that leads to activation of kidney tubulogenesis via Wnt-4. ..
  20. Lee H, Pazin D, Kahlon R, Correa S, Albrecht K. Novel markers of early ovarian pre-granulosa cells are expressed in an Sry-like pattern. Dev Dyn. 2009;238:812-25 pubmed publisher
    ..markers, 1700106J16Rik and Sprr2d, whose expression is ovary-biased during early gonad development, and altered in Wnt4, Sf1, Wt1, and Fog2 mutant gonads...
  21. Lin Y, Liu A, Zhang S, Ruusunen T, Kreidberg J, Peltoketo H, et al. Induction of ureter branching as a response to Wnt-2b signaling during early kidney organogenesis. Dev Dyn. 2001;222:26-39 pubmed
    ..In addition, Wnt signals in the kidney differ qualitatively and are specific to either the epithelial ureteric bud or the kidney mesenchyme. ..
  22. Staal F, Meeldijk J, Moerer P, Jay P, van de Weerdt B, Vainio S, et al. Wnt signaling is required for thymocyte development and activates Tcf-1 mediated transcription. Eur J Immunol. 2001;31:285-93 pubmed
    ..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 ..
  23. Miyakoshi T, Kajiya H, Miyajima K, Takei M, Tobita M, Takekoshi S, et al. The expression of Wnt4 is regulated by estrogen via an estrogen receptor alpha-dependent pathway in rat pituitary growth hormone-producing cells. Acta Histochem Cytochem. 2009;42:205-13 pubmed publisher
    Wnt signaling is important in many aspects of cell biology and development. In the mouse female reproductive tract, Wnt4, Wnt5a, and Wnt7a show differential expression during the estrus cycle, suggesting that they participate in female ..
  24. Liu C, Parker K, Yao H. WNT4/beta-catenin pathway maintains female germ cell survival by inhibiting activin betaB in the mouse fetal ovary. PLoS ONE. 2010;5:e10382 pubmed publisher
    ..We and others showed previously that when either Wnt4 or beta-catenin was inactivated in the fetal ovary, female germ cells underwent degeneration...
  25. Hua J, Xu Y, He Y, Jiang X, Ye W, Pan Z. Wnt4/β-catenin signaling pathway modulates balloon-injured carotid artery restenosis via disheveled-1. Int J Clin Exp Pathol. 2014;7:8421-31 pubmed
    ..To evaluate whether disheveled-1 (Dvl-1) is involved in the Wnt4/β-catenin signaling pathway to participate in the mechanisms of vascular restenosis...
  26. Kelly J, Kleemann D, Rudiger S, Walker S. Effects of grade of oocyte-cumulus complex and the interactions between grades on the production of blastocysts in the cow, ewe and lamb. Reprod Domest Anim. 2007;42:577-82 pubmed
  27. Fan C, Lee C, Tessier Lavigne M. A role for WNT proteins in induction of dermomyotome. Dev Biol. 1997;191:160-5 pubmed
    ..The documented expression of Wnt1 and Wnt3a in the dorsal neural tube and of Wnt4 and Wnt6 in the surface ectoderm at the time of dermomyotome specification prompted us to investigate the ..
  28. Zhou S, Eid K, Glowacki J. Cooperation between TGF-beta and Wnt pathways during chondrocyte and adipocyte differentiation of human marrow stromal cells. J Bone Miner Res. 2004;19:463-70 pubmed
    ..by macroarray, RT-PCR, and Western blot, TGF-beta activated genes in the TGF-beta/Smad pathway, upregulated Wnt2, Wnt4, Wnt5a, Wnt7a, Wnt10a, and Wnt co-receptor LRP5, and increased nuclear accumulation and stability of beta-catenin ..
  29. Huguet E, McMahon J, McMahon A, Bicknell R, Harris A. 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. Cancer Res. 1994;54:2615-21 pubmed
    ..We report the expression of Wnt3, Wnt4, and Wnt7b in human breast cell lines and Wnt2, Wnt3, Wnt4, and Wnt7b in human breast tissues...
  30. Rognoni E, Widmaier M, Jakobson M, Ruppert R, Ussar S, Katsougkri D, et al. Kindlin-1 controls Wnt and TGF-? availability to regulate cutaneous stem cell proliferation. Nat Med. 2014;20:350-9 pubmed publisher
    ..Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-?-mediated growth-inhibitory signals and Wnt-?-catenin-mediated growth-promoting signals. ..
  31. Biason Lauber A, Konrad D, Navratil F, Schoenle E. A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman. N Engl J Med. 2004;351:792-8 pubmed
    b>WNT4, a secreted protein that suppresses male sexual differentiation, is thought to repress the biosynthesis of gonadal androgen in female mammals...
  32. Naillat F, Prunskaite Hyyryläinen R, Pietilä I, Sormunen R, Jokela T, Shan J, et al. Wnt4/5a signalling coordinates cell adhesion and entry into meiosis during presumptive ovarian follicle development. Hum Mol Genet. 2010;19:1539-50 pubmed publisher
    ..These findings indicate a critical role for Wnt signalling in meiosis. Thus, the Wnt signals are important somatic cell signals that coordinate presumptive female follicle development. ..
  33. Wang L, Shao Y, Ballock R. Thyroid hormone-mediated growth and differentiation of growth plate chondrocytes involves IGF-1 modulation of beta-catenin signaling. J Bone Miner Res. 2010;25:1138-46 pubmed publisher
  34. Terada Y, Tanaka H, Okado T, Shimamura H, Inoshita S, Kuwahara M, et al. Expression and function of the developmental gene Wnt-4 during experimental acute renal failure in rats. J Am Soc Nephrol. 2003;14:1223-33 pubmed
    ..The Wnt-4-beta-catenin pathway may regulate the transcription of cyclin D1 and control the regeneration of renal tubules in ARF. ..
  35. Zhu D, Yu H, He H, Ding J, Tang J, Cao D, et al. Spironolactone inhibits apoptosis in rat mesangial cells under hyperglycaemic conditions via the Wnt signalling pathway. Mol Cell Biochem. 2013;380:185-93 pubmed publisher
    ..SPI promoted activation of the Wnt signalling pathway in MCs, leading to upregulation of Wnt4 and Wnt5a mRNA expression, decreased GSK-3? protein expression and increased ?-catenin protein expression...
  36. Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier M, et al. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biol. 2006;4:e187 pubmed
    ..In the mouse, Fgf9 and Wnt4 are expressed in gonads of both sexes prior to sex determination...
  37. Chang J, Sonoyama W, Wang Z, Jin Q, Zhang C, Krebsbach P, et al. Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK. J Biol Chem. 2007;282:30938-48 pubmed
    ..Taken together, our results reveal that noncanonical Wnt signaling could also play a role in osteogenic differentiation. Wnt-4 may have a potential use in improving bone regeneration and repair of craniofacial defects. ..
  38. Filippone M, Di Palma T, Lucci V, Zannini M. Pax8 modulates the expression of Wnt4 that is necessary for the maintenance of the epithelial phenotype of thyroid cells. BMC Mol Biol. 2014;15:21 pubmed publisher
    ..of the gene expression profile of FRTL-5 differentiated thyroid cells after the silencing of Pax8 identified Wnt4 as a novel target...
  39. van Amerongen R, Mikels A, Nusse R. Alternative wnt signaling is initiated by distinct receptors. Sci Signal. 2008;1:re9 pubmed publisher
    ..Here, we discuss basic principles of signal transduction initiated at the cell membrane, with the Wnt pathway, which harbors a multitude of ligands and receptors, as an example. ..
  40. Suwa T, Chen M, Hawks C, Hornsby P. Zonal expression of dickkopf-3 and components of the Wnt signalling pathways in the human adrenal cortex. J Endocrinol. 2003;178:149-58 pubmed
    ..Consistent with previously published data on the effects of Wnt4 gene disruption in the mouse, we found only WNT4 expression within the WNT family in both human and mouse RNA...
  41. Karner C, Das A, Ma Z, Self M, Chen C, Lum L, et al. Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development. Development. 2011;138:1247-57 pubmed publisher
    ..These findings provide novel insights into the molecular mechanisms that regulate progenitor cell differentiation during normal and pathological conditions. ..
  42. Bui T, Zhang L, Rees M, Bicknell R, Harris A. Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma. Br J Cancer. 1997;75:1131-6 pubmed
    ..b>Wnt4 was expressed in only one out of four cell lines (RL95-2), and Wnt5a was much lower...