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Gene Review

Wnt3a  -  wingless-type MMTV integration site family...

Mus musculus

Synonyms: Protein Wnt-3a, Wnt-3a, vt
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Disease relevance of Wnt3a


High impact information on Wnt3a

  • Wnt-1 and a related gene, Wnt-3a, are coexpressed from early somite stages in dorsal aspects of the myelencephalon and spinal cord [3].
  • The purified Wnt3a protein induces self-renewal of haematopoietic stem cells, signifying its potential use in tissue engineering [4].
  • Here we demonstrate that in the absence of both Wnt- and Wnt-3a there is a marked deficiency in neural crest derivatives, which originate from the dorsal neural tube, and a pronounced reduction in dorsolateral neural precursors within the neural tube itself [5].
  • Expression of T (Brachyury) and Wnt3a in the tailbud was down-regulated in CYP26(-/-) mice, which may underlie the caudal truncation [6].
  • Here we show that null mutations in both Lef1 and Tcf1, which are expressed in an overlapping pattern in the early mouse embryo, cause a severe defect in the differentiation of paraxial mesoderm and lead to the formation of additional neural tubes, phenotypes identical to those reported for Wnt3a-deficient mice [7].

Biological context of Wnt3a


Anatomical context of Wnt3a

  • T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification [12].
  • Wnt3a encodes a signal that is expressed in the primitive streak of the gastrulating mouse embryo and is required for paraxial mesoderm development [12].
  • 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 [13].
  • Differentiation of the most dorsal neural plate, which gives rise to both roof plate and neural crest cells, also was delayed as indicated by the expression lag of a roof plate marker, Wnt3a [14].
  • Analysis of the neuronal differentiation of embryonic stem cells revealed that Wnt3a redirects the fate of neural progenitors to a posterior character, whereas ICAT induces forebrain cells by inhibiting Wnt signaling [15].

Associations of Wnt3a with chemical compounds

  • We have previously shown that retinoic acid plays a key role in early stages of Cdx1 expression at embryonic day 7.5 (E7.5), while both Wnt3a signaling and an autoregulatory loop, dependent on Cdx1 itself, are involved in later stages of expression (E8.5 to E9.5) [16].
  • Finally, the enhanced gene expression of alkaline phosphatase induced by Wnt-3a could be effectively suppressed by the combined action of dexamethasone and 1,25-dihydroxyvitamin D(3) [17].
  • In co-cultures of mouse mononuclear spleen cells and osteoblasts, inhibition of GSK3beta with LiCl or exposure to Wnt3a inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated cells compared with controls [18].
  • Wnt-1 and Wnt-3a, which encode members of the Wnt family of cystein-rich secreted signaling molecules, are coexpressed at the dorsal midline of the developing neural tube, an area adjacent to the dorsomedial portion of the somite [19].
  • Moreover, the neurotoxic effect of Abeta fibrils was also modulated with protein kinase C agonists/inhibitors and reversed with conditioned medium containing the Wnt-3a ligand [20].
  • Molecular interaction analyses using Biacore revealed that squid CS-E (rich in the E disaccharide unit) bound strongly to Wnt-3a (K(d)=13.2 nm) to the same extent as heparin from bovine lung (K(d)=8.43 nm) [21].

Physical interactions of Wnt3a


Regulatory relationships of Wnt3a

  • We showed that expression of matrix extracellular phosphoglycoprotein was induced by BMP-2 in Wnt3a over-expressing C2C12 cells but not in Wnt5a over-expressing C2C12 cells [23].
  • Moreover, BMP-2 enhanced Wntl and Wnt3a expression in our cells [24].
  • Here we show that Brachyury is specifically down-regulated in Wnt3a mutants in cells fated to form paraxial mesoderm [12].
  • In GSK3alpha/GSK3beta homozygous knockin cells, Wnt3a induces normal inactivation of GSK3, as judged by the stabilisation of beta-catenin and stimulation of Wnt-dependent transcription [25].
  • Over-expression of Wnt3a blocked BMP-2-induced inhibition of myotube formation in C2C12 cells when switched to low mitogen medium [23].

Other interactions of Wnt3a

  • In the tail bud, reduced expression of Wnt3a and Dll1 correlates with phenotypic severity of caudal regression [26].
  • By contrast, three others, Wnt3a, 5a and a novel mouse Wnt gene, Wnt2b, are expressed only at the medial edge of the telencephalon, defining the hem of the cerebral cortex [27].
  • Wnt3a and Wnt7a were absent in the cell lines and tissues tested [28].
  • At least three genes (Wnt-3, Wnt-3a, and Wnt-7b) exhibit sharp boundaries of expression in the forebrain that may predict subdivisions of the region later in development [29].
  • We found that Cdx4 responds to exogenous Wnt3a in mouse embryos ex vivo, and conversely, that its expression is down-regulated in Wnt3a(vt/vt) embryos and in embryos cultured in the presence of Wnt inhibitors [30].

Analytical, diagnostic and therapeutic context of Wnt3a


  1. The expression of the mouse Zic1, Zic2, and Zic3 gene suggests an essential role for Zic genes in body pattern formation. Nagai, T., Aruga, J., Takada, S., Günther, T., Spörle, R., Schughart, K., Mikoshiba, K. Dev. Biol. (1997) [Pubmed]
  2. Wnt/beta-catenin signaling suppresses apoptosis in low serum medium and induces morphologic change in rodent fibroblasts. Ueda, Y., Hijikata, M., Takagi, S., Takada, R., Takada, S., Chiba, T., Shimotohno, K. Int. J. Cancer (2002) [Pubmed]
  3. 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]
  4. Wnt proteins are lipid-modified and can act as stem cell growth factors. Willert, K., Brown, J.D., Danenberg, E., Duncan, A.W., Weissman, I.L., Reya, T., Yates, J.R., Nusse, R. Nature (2003) [Pubmed]
  5. Wnt signalling required for expansion of neural crest and CNS progenitors. Ikeya, M., Lee, S.M., Johnson, J.E., McMahon, A.P., Takada, S. Nature (1997) [Pubmed]
  6. The retinoic acid-inactivating enzyme CYP26 is essential for establishing an uneven distribution of retinoic acid along the anterio-posterior axis within the mouse embryo. Sakai, Y., Meno, C., Fujii, H., Nishino, J., Shiratori, H., Saijoh, Y., Rossant, J., Hamada, H. Genes Dev. (2001) [Pubmed]
  7. Wnt3a-/--like phenotype and limb deficiency in Lef1(-/-)Tcf1(-/-) mice. Galceran, J., Fariñas, I., Depew, M.J., Clevers, H., Grosschedl, R. Genes Dev. (1999) [Pubmed]
  8. Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Tickenbrock, L., Schwäble, J., Wiedehage, M., Steffen, B., Sargin, B., Choudhary, C., Brandts, C., Berdel, W.E., Müller-Tidow, C., Serve, H. Blood (2005) [Pubmed]
  9. Developing with lethal RA levels: genetic ablation of Rarg can restore the viability of mice lacking Cyp26a1. Abu-Abed, S., Dollé, P., Metzger, D., Wood, C., MacLean, G., Chambon, P., Petkovich, M. Development (2003) [Pubmed]
  10. Wnt signaling inhibits adipogenesis through beta-catenin-dependent and -independent mechanisms. Kennell, J.A., MacDougald, O.A. J. Biol. Chem. (2005) [Pubmed]
  11. Both ERK and Wnt/beta-catenin pathways are involved in Wnt3a-induced proliferation. Yun, M.S., Kim, S.E., Jeon, S.H., Lee, J.S., Choi, K.Y. J. Cell. Sci. (2005) [Pubmed]
  12. T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification. Yamaguchi, T.P., Takada, S., Yoshikawa, Y., Wu, N., McMahon, A.P. Genes Dev. (1999) [Pubmed]
  13. 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]
  14. Zic2 regulates the kinetics of neurulation. Nagai, T., Aruga, J., Minowa, O., Sugimoto, T., Ohno, Y., Noda, T., Mikoshiba, K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  15. Anteriorization of neural fate by inhibitor of beta-catenin and T cell factor (ICAT), a negative regulator of Wnt signaling. Satoh, K., Kasai, M., Ishidao, T., Tago, K., Ohwada, S., Hasegawa, Y., Senda, T., Takada, S., Nada, S., Nakamura, T., Akiyama, T. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  16. Cdx1 autoregulation is governed by a novel Cdx1-LEF1 transcription complex. Béland, M., Pilon, N., Houle, M., Oh, K., Sylvestre, J.R., Prinos, P., Lohnes, D. Mol. Cell. Biol. (2004) [Pubmed]
  17. Differential regulation of osteogenic marker gene expression by Wnt-3a in embryonic mesenchymal multipotential progenitor cells. Derfoul, A., Carlberg, A.L., Tuan, R.S., Hall, D.J. Differentiation (2004) [Pubmed]
  18. Wnt signalling in osteoblasts regulates expression of the receptor activator of NFkappaB ligand and inhibits osteoclastogenesis in vitro. Spencer, G.J., Utting, J.C., Etheridge, S.L., Arnett, T.R., Genever, P.G. J. Cell. Sci. (2006) [Pubmed]
  19. Wnt signaling from the dorsal neural tube is required for the formation of the medial dermomyotome. Ikeya, M., Takada, S. Development (1998) [Pubmed]
  20. Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. De Ferrari, G.V., Chacón, M.A., Barría, M.I., Garrido, J.L., Godoy, J.A., Olivares, G., Reyes, A.E., Alvarez, A., Bronfman, M., Inestrosa, N.C. Mol. Psychiatry (2003) [Pubmed]
  21. Chondroitin 4-O-sulfotransferase-1 modulates Wnt-3a signaling through control of E disaccharide expression of chondroitin sulfate. Nadanaka, S., Ishida, M., Ikegami, M., Kitagawa, H. J. Biol. Chem. (2008) [Pubmed]
  22. Wnt-3a regulates chondrocyte differentiation via c-Jun/AP-1 pathway. Hwang, S.G., Yu, S.S., Lee, S.W., Chun, J.S. FEBS Lett. (2005) [Pubmed]
  23. Cross-talk between Wnt and bone morphogenetic protein 2 (BMP-2) signaling in differentiation pathway of C2C12 myoblasts. Nakashima, A., Katagiri, T., Tamura, M. J. Biol. Chem. (2005) [Pubmed]
  24. BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. Rawadi, G., Vayssière, B., Dunn, F., Baron, R., Roman-Roman, S. J. Bone Miner. Res. (2003) [Pubmed]
  25. Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. McManus, E.J., Sakamoto, K., Armit, L.J., Ronaldson, L., Shpiro, N., Marquez, R., Alessi, D.R. EMBO J. (2005) [Pubmed]
  26. Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator. Keegan, C.E., Hutz, J.E., Else, T., Adamska, M., Shah, S.P., Kent, A.E., Howes, J.M., Beamer, W.G., Hammer, G.D. Hum. Mol. Genet. (2005) [Pubmed]
  27. The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice. Grove, E.A., Tole, S., Limon, J., Yip, L., Ragsdale, C.W. Development (1998) [Pubmed]
  28. 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]
  29. Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds. Parr, B.A., Shea, M.J., Vassileva, G., McMahon, A.P. Development (1993) [Pubmed]
  30. Cdx4 is a direct target of the canonical Wnt pathway. Pilon, N., Oh, K., Sylvestre, J.R., Bouchard, N., Savory, J., Lohnes, D. Dev. Biol. (2006) [Pubmed]
  31. Decreased neural crest stem cell expansion is responsible for the conotruncal heart defects within the splotch (Sp(2H))/Pax3 mouse mutant. Conway, S.J., Bundy, J., Chen, J., Dickman, E., Rogers, R., Will, B.M. Cardiovasc. Res. (2000) [Pubmed]
  32. Wnt-3a regulates somite and tailbud formation in the mouse embryo. Takada, S., Stark, K.L., Shea, M.J., Vassileva, G., McMahon, J.A., McMahon, A.P. Genes Dev. (1994) [Pubmed]
  33. Axin prevents Wnt-3a-induced accumulation of beta-catenin. Kishida, M., Koyama, S., Kishida, S., Matsubara, K., Nakashima, S., Higano, K., Takada, R., Takada, S., Kikuchi, A. Oncogene (1999) [Pubmed]
  34. Phosphatidylinositol 3-kinase-Akt pathway plays a critical role in early cardiomyogenesis by regulating canonical Wnt signaling. Naito, A.T., Akazawa, H., Takano, H., Minamino, T., Nagai, T., Aburatani, H., Komuro, I. Circ. Res. (2005) [Pubmed]
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