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Gene Review

Wnt1  -  wingless-type MMTV integration site family...

Mus musculus

Synonyms: Int-1, Proto-oncogene Int-1, Proto-oncogene Wnt-1, Wnt-1, sw, ...
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Disease relevance of Wnt1

  • Notably, we found mucous cell metaplasia in the glandular stomach of the K19-Wnt1/C2mE mice as early as 5 weeks of age, before the dysplastic tumor development [1].
  • Neural crest derivatives from rhombomere 6, such as the glossopharyngeal ganglion, are defective, and the dorsal neural tube marker Wnt1 is absent from this segment [2].
  • Our results indicate that several of the Wnt ligands, especially Wnt1 and Wnt6, are strongly expressed in both normal and malignant breast tissue and that Wnt7b is down-regulated in breast cancer, compared to normal breast epithelium [3].
  • BACKGROUND: MMTV-Wnt1 transgenic mice develop mammary hyperplasia early in development, followed by the appearance of solitary mammary tumors with a high proportion of cells expressing early lineage markers and many myoepithelial cells [4].
  • To induce such events and to identify the genes involved, we have infected Wnt-1 transgenic mice with mouse mammary tumor virus (MMTV), intending to insertionally activate, and thereby molecularly tag, cooperating protooncogenes [5].

High impact information on Wnt1


Chemical compound and disease context of Wnt1


Biological context of Wnt1


Anatomical context of Wnt1

  • We further show that the source of Wnt impacting on dorsal otic development emanates from the dorsal hindbrain, and identify Wnt1 and Wnt3a as the specific ligands required for this function [16].
  • In Six3(-/-) mice, the prosencephalon was severely truncated, and the expression of Wnt1 was rostrally expanded, a finding that indicates that the mutant head was posteriorized [17].
  • Mice deficient for both Wnt1 and Wnt3a have a marked deficiency in trunk neural crest derivatives including NC-Ms [18].
  • Neural crest-directed gene transfer demonstrates Wnt1 role in melanocyte expansion and differentiation during mouse development [18].
  • In contrast, ectopic expression of Fgf8a in the mouse midbrain and caudal forebrain using a Wnt1 regulatory element produced no apparent patterning defects in the embryos examined (Lee, S. M., Danielian, P. S., Fritzsch, B. and McMahon, A. P. (1997) Development 124, 959-969) [19].

Associations of Wnt1 with chemical compounds

  • Using the enhancer of the Wnt1 gene to restrict the expression of Cre-ERTM to the embryonic neural tube, we found that a single injection of tamoxifen into pregnant mice induced Cre-mediated recombination within the embryonic central nervous system, thereby activating expression of a reporter gene [20].
  • Moreover, the soluble cysteine-rich domain of Frizzled-8 (a Wnt inhibitor) blocked endogenous Wnts and the effects of Wnt-1 and -5a on proliferation and the acquisition of a DA phenotype in precursor cultures [21].
  • Specifically, loss of one p53 allele dramatically facilitates the progression of mammary tumors to a Wnt1-independent state both by impairing the regression of primary tumors following doxycycline withdrawal and by promoting the recurrence of fully regressed tumors in the absence of doxycycline [22].
  • The secreted glycoprotein Wnt1 is expressed in close vicinity to developing midbrain dopaminergic neurons [23].
  • These results suggest that mammary stem cells and/or progenitors to mammary luminal epithelial and myoepithelial cells may be the targets for oncogenesis by Wnt-1 signaling elements [24].

Physical interactions of Wnt1


Regulatory relationships of Wnt1


Other interactions of Wnt1

  • These findings provide further evidence that fibroblast growth factors Int-2 and Hst can cooperate with Wnt-1, another secreted factor, in mammary tumorigenesis, and they illustrate the capacity of this system to identify cooperating oncogenes [5].
  • FGF8 and WNT1 have been implicated as key components of IsO signaling activity, and previous studies have shown that in Wnt1(-/-) embryos, the mes/met is deleted by the 30 somite stage ( approximately E10) (McMahon, A. P. and Bradley, A. (1990) Cell 62, 1073-1085) [15].
  • Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice [32].
  • Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia [33].
  • Sonic Hedgehog synergises with both Wnt1 and Wnt7a in explants from E8.5 paraxial mesoderm but not in explants from E9.5 embryos [34].

Analytical, diagnostic and therapeutic context of Wnt1

  • Co-culture experiments with NIH3T3 cells showed that the co-expression of Wnt11 with Wnt1 was not an essential requirement for the inhibition, suggesting receptor competition as a possible mechanism [29].
  • Transduction of fetal thymocytes with Wnt1 and Wnt4 results in increased survival in an in vitro cell culture system [35].
  • Using DNA microarray analysis, we identified several genes that are regulated by Wnt-5a and Rfz-2 as well as by Wnt-1 [36].
  • Histological examination shows that sw is phenotypically identical to a previously described wnt-1 mutation introduced into mice by gene targeting [37].
  • Prepubertal ovariectomy of Wnt-1 TG mice also extended tumor latency to 42 weeks [38].


  1. Carcinogenesis in mouse stomach by simultaneous activation of the wnt signaling and prostaglandin e(2) pathway. Oshima, H., Matsunaga, A., Fujimura, T., Tsukamoto, T., Taketo, M.M., Oshima, M. Gastroenterology (2006) [Pubmed]
  2. Dorsal patterning defects in the hindbrain, roof plate and skeleton in the dreher (dr(J)) mouse mutant. Manzanares, M., Trainor, P.A., Ariza-McNaughton, L., Nonchev, S., Krumlauf, R. Mech. Dev. (2000) [Pubmed]
  3. Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma. Milovanovic, T., Planutis, K., Nguyen, A., Marsh, J.L., Lin, F., Hope, C., Holcombe, R.F. Int. J. Oncol. (2004) [Pubmed]
  4. Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype. Podsypanina, K., Li, Y., Varmus, H.E. BMC medicine [electronic resource]. (2004) [Pubmed]
  5. Mouse mammary tumor virus infection accelerates mammary carcinogenesis in Wnt-1 transgenic mice by insertional activation of int-2/Fgf-3 and hst/Fgf-4. Shackleford, G.M., MacArthur, C.A., Kwan, H.C., Varmus, H.E. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  6. Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice. Alexander, C.M., Reichsman, F., Hinkes, M.T., Lincecum, J., Becker, K.A., Cumberledge, S., Bernfield, M. Nat. Genet. (2000) [Pubmed]
  7. Frzb-1 is a secreted antagonist of Wnt signaling expressed in the Spemann organizer. Leyns, L., Bouwmeester, T., Kim, S.H., Piccolo, S., De Robertis, E.M. Cell (1997) [Pubmed]
  8. The midbrain-hindbrain phenotype of Wnt-1-/Wnt-1- mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum. McMahon, A.P., Joyner, A.L., Bradley, A., McMahon, J.A. Cell (1992) [Pubmed]
  9. Dormant wnt-initiated mammary cancer can participate in reconstituting functional mammary glands. Gestl, S.A., Leonard, T.L., Biddle, J.L., Debies, M.T., Gunther, E.J. Mol. Cell. Biol. (2007) [Pubmed]
  10. Expression and regulation of WNT1 in human cancer: up-regulation of WNT1 by beta-estradiol in MCF-7 cells. Katoh, M. Int. J. Oncol. (2003) [Pubmed]
  11. Wnt-1 inhibits nerve growth factor-induced differentiation of PC12 cells by preventing the induction of some but not all late-response genes. Chou, A.H., Zheng, S., Itsukaichi, T., Howard, B.D. Brain Res. Mol. Brain Res. (2000) [Pubmed]
  12. The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney. Favor, J., Sandulache, R., Neuhäuser-Klaus, A., Pretsch, W., Chatterjee, B., Senft, E., Wurst, W., Blanquet, V., Grimes, P., Spörle, R., Schughart, K. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  13. Wnt proteins induce dishevelled phosphorylation via an LRP5/6- independent mechanism, irrespective of their ability to stabilize beta-catenin. González-Sancho, J.M., Brennan, K.R., Castelo-Soccio, L.A., Brown, A.M. Mol. Cell. Biol. (2004) [Pubmed]
  14. Myf5 is a novel early axonal marker in the mouse brain and is subjected to post-transcriptional regulation in neurons. Daubas, P., Tajbakhsh, S., Hadchouel, J., Primig, M., Buckingham, M. Development (2000) [Pubmed]
  15. The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum. Chi, C.L., Martinez, S., Wurst, W., Martin, G.R. Development (2003) [Pubmed]
  16. Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh. Riccomagno, M.M., Takada, S., Epstein, D.J. Genes Dev. (2005) [Pubmed]
  17. Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development. Lagutin, O.V., Zhu, C.C., Kobayashi, D., Topczewski, J., Shimamura, K., Puelles, L., Russell, H.R., McKinnon, P.J., Solnica-Krezel, L., Oliver, G. Genes Dev. (2003) [Pubmed]
  18. Neural crest-directed gene transfer demonstrates Wnt1 role in melanocyte expansion and differentiation during mouse development. Dunn, K.J., Williams, B.O., Li, Y., Pavan, W.J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  19. FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate. Liu, A., Losos, K., Joyner, A.L. Development (1999) [Pubmed]
  20. Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Danielian, P.S., Muccino, D., Rowitch, D.H., Michael, S.K., McMahon, A.P. Curr. Biol. (1998) [Pubmed]
  21. Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. Castelo-Branco, G., Wagner, J., Rodriguez, F.J., Kele, J., Sousa, K., Rawal, N., Pasolli, H.A., Fuchs, E., Kitajewski, J., Arenas, E. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  22. Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. Gunther, E.J., Moody, S.E., Belka, G.K., Hahn, K.T., Innocent, N., Dugan, K.D., Cardiff, R.D., Chodosh, L.A. Genes Dev. (2003) [Pubmed]
  23. A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo. Prakash, N., Brodski, C., Naserke, T., Puelles, E., Gogoi, R., Hall, A., Panhuysen, M., Echevarria, D., Sussel, L., Weisenhorn, D.M., Martinez, S., Arenas, E., Simeone, A., Wurst, W. Development (2006) [Pubmed]
  24. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Li, Y., Welm, B., Podsypanina, K., Huang, S., Chamorro, M., Zhang, X., Rowlands, T., Egeblad, M., Cowin, P., Werb, Z., Tan, L.K., Rosen, J.M., Varmus, H.E. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  25. LeX is expressed by principle progenitor cells in the embryonic nervous system, is secreted into their environment and binds Wnt-1. Capela, A., Temple, S. Dev. Biol. (2006) [Pubmed]
  26. Two members of the Tcf family implicated in Wnt/beta-catenin signaling during embryogenesis in the mouse. Korinek, V., Barker, N., Willert, K., Molenaar, M., Roose, J., Wagenaar, G., Markman, M., Lamers, W., Destree, O., Clevers, H. Mol. Cell. Biol. (1998) [Pubmed]
  27. Evidence that FGF8 signalling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain. Lee, S.M., Danielian, P.S., Fritzsch, B., McMahon, A.P. Development (1997) [Pubmed]
  28. Msx1 is required for dorsal diencephalon patterning. Bach, A., Lallemand, Y., Nicola, M.A., Ramos, C., Mathis, L., Maufras, M., Robert, B. Development (2003) [Pubmed]
  29. Multiple mechanisms for Wnt11-mediated repression of the canonical Wnt signaling pathway. Maye, P., Zheng, J., Li, L., Wu, D. J. Biol. Chem. (2004) [Pubmed]
  30. Murine Frizzled-1 behaves as an antagonist of the canonical Wnt/beta-catenin signaling. Roman-Roman, S., Shi, D.L., Stiot, V., Haÿ, E., Vayssière, B., Garcia, T., Baron, R., Rawadi, G. J. Biol. Chem. (2004) [Pubmed]
  31. Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models. Du, Z., Podsypanina, K., Huang, S., McGrath, A., Toneff, M.J., Bogoslovskaia, E., Zhang, X., Moraes, R.C., Fluck, M., Allred, D.C., Lewis, M.T., Varmus, H.E., Li, Y. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  32. Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice. Guo, C., Qiu, H.Y., Huang, Y., Chen, H., Yang, R.Q., Chen, S.D., Johnson, R.L., Chen, Z.F., Ding, Y.Q. Development (2007) [Pubmed]
  33. Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia. Ligon, K.L., Echelard, Y., Assimacopoulos, S., Danielian, P.S., Kaing, S., Grove, E.A., McMahon, A.P., Rowitch, D.H. Development (2003) [Pubmed]
  34. Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5. Tajbakhsh, S., Borello, U., Vivarelli, E., Kelly, R., Papkoff, J., Duprez, D., Buckingham, M., Cossu, G. Development (1998) [Pubmed]
  35. 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]
  36. Stromelysin-1 and mesothelin are differentially regulated by Wnt-5a and Wnt-1 in C57mg mouse mammary epithelial cells. Prieve, M.G., Moon, R.T. BMC Dev. Biol. (2003) [Pubmed]
  37. Swaying is a mutant allele of the proto-oncogene Wnt-1. Thomas, K.R., Musci, T.S., Neumann, P.E., Capecchi, M.R. Cell (1991) [Pubmed]
  38. A mouse mammary tumor virus-Wnt-1 transgene induces mammary gland hyperplasia and tumorigenesis in mice lacking estrogen receptor-alpha. Bocchinfuso, W.P., Hively, W.P., Couse, J.F., Varmus, H.E., Korach, K.S. Cancer Res. (1999) [Pubmed]
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