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Gene Review

Wnt4  -  Wnt oncogene analog 4

Drosophila melanogaster

Synonyms: CG4698, DWnt-4, DWnt4, Dm DWnt4, Dmel\CG4698, ...
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Disease relevance of Wnt4

  • Deregulation of the Wg/Wnt pathway has been causally linked to several forms of cancer, most notably to colorectal cancer [1].
  • Recent studies have suggested an association between excess signaling through the canonical Wnt pathway and osteoarthritis (OA) [2].
  • Aberrant Wnt signaling impacts nearly the entire spectrum of human disease, including birth defects, cancer, and osteoporosis [3].
  • Deficiency of Wnt-4, -5a, and -7a, for example, results in sex reversal, infertility, and/or malformation of the internal and external genitals [4].
  • These data indicate that amplification and increased expression of the DVL-1 gene may play some role in the development of a portion of human cervical squamous cell cancer through derangement of the Wnt signaling pathway [5].

Psychiatry related information on Wnt4


High impact information on Wnt4

  • Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth [7].
  • Several recent papers reveal new insights into the mechanisms by which cells turn their perceptions about fate into action, focusing on the role of Wnt signal transduction in cell polarization and migration [8].
  • Wnt/Wingless directs many cell fates during development [9].
  • Recent genetic studies in Drosophila have begun to clarify the function of HSPGs in vivo and recent findings have implicated HSPGs in Wnt, Hedgehog, fibroblast growth factor and transforming growth factor-beta signaling pathways during development [10].
  • Dfrizzled2 and dishevelled, respectively, encode a receptor and a signaling molecule required for Wnt signaling [11].

Biological context of Wnt4


Anatomical context of Wnt4

  • DWnt-4, a novel Drosophila Wnt gene acts downstream of homeotic complex genes in the visceral mesoderm [17].
  • Our murine model provides a useful platform to study human MDS/AML transformation, as well as the Wnt/beta-catenin pathway's role in the pathogenesis of leukemia stem cells [18].
  • csal1 is controlled by a combination of FGF and Wnt signals in developing limb buds [19].
  • Antagonist activity of DWnt-4 and wingless in the Drosophila embryonic ventral ectoderm and in heterologous Xenopus assays [20].
  • Alteration of matrix glycosaminoglycans diminishes articular chondrocytes' response to a canonical Wnt signal [2].

Associations of Wnt4 with chemical compounds

  • CONCLUSION: This study demonstrates that articular chondrocytes respond to canonical Wnt stimulation, and that reduced sulfation or CS content diminishes that response [2].
  • Our results suggest that Wnt-like ligands may bind to these developmental tyrosine kinases[21]
  • The Frizzled genes belong to the seven transmembrane class of receptors (7TMR) and have on their extracellular region a cysteine-rich domain that has been implicated as the Wnt binding domain [21].
  • Heterotrimeric guanine nucleotide-binding proteins (G proteins) and RGS proteins have been implicated in Wnt signaling [22].

Regulatory relationships of Wnt4

  • Ectopic expression of DWnt4 in the dorsoventral (DV) polar margins is insufficient to induce ommatidial polarity but becomes inductive when coexpressed with Four-jointed (Fj) [13].
  • In Xenopus, however, overexpression of C-terminally truncated beta-catenin activates Wnt signaling, suggesting that the C-terminal domain might not be essential [23].
  • We provide evidence that DWnt-4 inhibits the Wingless/Wnt-1 signalling pathway upstream of the activation of transcriptional targets [20].

Other interactions of Wnt4

  • Whereas wingless acts independently of hedgehog signaling in these cells, we show that DWnt-4 requires Hh to elicit its effects [14].
  • JNK activity is necessary and sufficient for axon extension, whereas the antagonistic Wnt and FGF signals act to balance the extension and retraction required for the generation of the precise wiring pattern [24].
  • In contrast to the synergy between DWnt4 and Fj, DWnt4 antagonizes the polarizing effect of Fz [13].
  • From a library of DNA fragments associated, in vivo, with Ultrabithorax proteins, we isolated a novel Drosophila Wnt gene, DWnt-4 [17].
  • The control of DWnt-4 expression in the visceral mesoderm involves a network of regulatory molecules that includes Ultrabithorax and other proteins from the homeotic complex (HOM-C), as well as the TGF-beta decapentaplegic gene product [17].

Analytical, diagnostic and therapeutic context of Wnt4

  • Recent work in cell culture has suggested that phosphorylation of Dsh by Casein Kinase I epsilon (CKIepsilon) may act as a molecular "switch," promoting Wnt/beta-catenin while inhibiting Fz/PCP signaling [25].


  1. BCL9-2 binds Arm/beta-catenin in a Tyr142-independent manner and requires Pygopus for its function in Wg/Wnt signaling. Hoffmans, R., Basler, K. Mech. Dev. (2007) [Pubmed]
  2. Alteration of matrix glycosaminoglycans diminishes articular chondrocytes' response to a canonical Wnt signal. Shortkroff, S., Yates, K.E. Osteoarthr. Cartil. (2007) [Pubmed]
  3. An unconventional nuclear localization motif is crucial for function of the Drosophila wnt/wingless antagonist naked cuticle. Waldrop, S., Chan, C.C., Cagatay, T., Zhang, S., Rousset, R., Mack, J., Zeng, W., Fish, M., Zhang, M., Amanai, M., Wharton, K.A. Genetics (2006) [Pubmed]
  4. Wnts and the female reproductive system. Heikkilä, M., Peltoketo, H., Vainio, S. J. Exp. Zool. (2001) [Pubmed]
  5. Up-regulation and overproduction of DVL-1, the human counterpart of the Drosophila dishevelled gene, in cervical squamous cell carcinoma. Okino, K., Nagai, H., Hatta, M., Nagahata, T., Yoneyama, K., Ohta, Y., Jin, E., Kawanami, O., Araki, T., Emi, M. Oncol. Rep. (2003) [Pubmed]
  6. The Wnt-dependent signaling pathways as target in oncology drug discovery. Janssens, N., Janicot, M., Perera, T. Investigational new drugs. (2006) [Pubmed]
  7. Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Lu, W., Yamamoto, V., Ortega, B., Baltimore, D. Cell (2004) [Pubmed]
  8. The ballet of morphogenesis: unveiling the hidden choreographers. Peifer, M., McEwen, D.G. Cell (2002) [Pubmed]
  9. Negative regulation of Wingless signaling by D-axin, a Drosophila homolog of axin. Hamada, F., Tomoyasu, Y., Takatsu, Y., Nakamura, M., Nagai, S., Suzuki, A., Fujita, F., Shibuya, H., Toyoshima, K., Ueno, N., Akiyama, T. Science (1999) [Pubmed]
  10. Functional binding of secreted molecules to heparan sulfate proteoglycans in Drosophila. Baeg, G.H., Perrimon, N. Curr. Opin. Cell Biol. (2000) [Pubmed]
  11. DWnt4 regulates the dorsoventral specificity of retinal projections in the Drosophila melanogaster visual system. Sato, M., Umetsu, D., Murakami, S., Yasugi, T., Tabata, T. Nat. Neurosci. (2006) [Pubmed]
  12. DWnt4 regulates cell movement and focal adhesion kinase during Drosophila ovarian morphogenesis. Cohen, E.D., Mariol, M.C., Wallace, R.M., Weyers, J., Kamberov, Y.G., Pradel, J., Wilder, E.L. Dev. Cell (2002) [Pubmed]
  13. Control of planar cell polarity by interaction of DWnt4 and four-jointed. Lim, J., Norga, K.K., Chen, Z., Choi, K.W. Genesis (2005) [Pubmed]
  14. DWnt-4 and Wingless have distinct activities in the Drosophila dorsal epidermis. Buratovich, M.A., Anderson, S., Gieseler, K., Pradel, J., Wilder, E.L. Dev. Genes Evol. (2000) [Pubmed]
  15. Drosophila split ends homologue SHARP functions as a positive regulator of Wnt/beta-catenin/T-cell factor signaling in neoplastic transformation. Feng, Y., Bommer, G.T., Zhai, Y., Akyol, A., Hinoi, T., Winer, I., Lin, H.V., Cadigan, K.M., Cho, K.R., Fearon, E.R. Cancer Res. (2007) [Pubmed]
  16. Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis. Naito, A.T., Shiojima, I., Akazawa, H., Hidaka, K., Morisaki, T., Kikuchi, A., Komuro, I. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  17. DWnt-4, a novel Drosophila Wnt gene acts downstream of homeotic complex genes in the visceral mesoderm. Graba, Y., Gieseler, K., Aragnol, D., Laurenti, P., Mariol, M.C., Berenger, H., Sagnier, T., Pradel, J. Development (1995) [Pubmed]
  18. SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Ma, Y., Cui, W., Yang, J., Qu, J., Di, C., Amin, H.M., Lai, R., Ritz, J., Krause, D.S., Chai, L. Blood (2006) [Pubmed]
  19. csal1 is controlled by a combination of FGF and Wnt signals in developing limb buds. Farrell, E.R., Münsterberg, A.E. Dev. Biol. (2000) [Pubmed]
  20. Antagonist activity of DWnt-4 and wingless in the Drosophila embryonic ventral ectoderm and in heterologous Xenopus assays. Gieseler, K., Graba, Y., Mariol, M.C., Wilder, E.L., Martinez-Arias, A., Lemaire, P., Pradel, J. Mech. Dev. (1999) [Pubmed]
  21. Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases. Saldanha, J., Singh, J., Mahadevan, D. Protein Sci. (1998) [Pubmed]
  22. Wnt signaling, Ca2+, and cyclic GMP: visualizing Frizzled functions. Wang, H.Y., Malbon, C.C. Science (2003) [Pubmed]
  23. Roles of the C terminus of Armadillo in Wingless signaling in Drosophila. Cox, R.T., Pai, L.M., Kirkpatrick, C., Stein, J., Peifer, M. Genetics (1999) [Pubmed]
  24. A signaling network for patterning of neuronal connectivity in the Drosophila brain. Srahna, M., Leyssen, M., Choi, C.M., Fradkin, L.G., Noordermeer, J.N., Hassan, B.A. PLoS Biol. (2006) [Pubmed]
  25. CKIepsilon/discs overgrown promotes both Wnt-Fz/beta-catenin and Fz/PCP signaling in Drosophila. Klein, T.J., Jenny, A., Djiane, A., Mlodzik, M. Curr. Biol. (2006) [Pubmed]
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