Stem Cell Reviews and Reports

, Volume 10, Issue 2, pp 207–229 | Cite as

Wnt Signaling and the Control of Human Stem Cell Fate

  • J. K. Van Camp
  • S. Beckers
  • D. Zegers
  • W. Van Hul


Wnt signaling determines major developmental processes in the embryonic state and regulates maintenance, self-renewal and differentiation of adult mammalian tissue stem cells. Both β-catenin dependent and independent Wnt pathways exist, and both affect stem cell fate in developing and adult tissues. In this review, we debate the response to Wnt signal activation in embryonic stem cells and human, adult stem cells of mesenchymal, hematopoetic, intestinal, gastric, epidermal, mammary and neural lineages, and discuss the need for Wnt signaling in these cell types. Due to the vital actions of Wnt signaling in developmental and maintenance processes, deregulation of the pathway can culminate into a broad spectrum of developmental and genetic diseases, including cancer. The way in which Wnt signals can feed tumors and maintain cancer stem stells is discussed as well. Manipulation of Wnt signals both in vivo and in vitro thus carries potential for therapeutic approaches such as tissue engineering for regenerative medicine and anti-cancer treatment. Although many questions remain regarding the complete Wnt signal cell-type specific response and interplay of Wnt signaling with pathways such as BMP, Hedgehog and Notch, we hereby provide an overview of current knowledge on Wnt signaling and its control over human stem cell fate.


Wnt Human Embryonic stem cells Adult stem cells Canonical Noncanonical 


Conflict of Interest

The authors declare no conflict of interest.


  1. 1.
    Nusse, R., & Varmus, H. E. (1982). Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 31, 99–109.PubMedGoogle Scholar
  2. 2.
    Bhanot, P., Brink, M., Samos, C. H., et al. (1996). A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature, 382, 225–230.PubMedGoogle Scholar
  3. 3.
    Bejsovec, A. (2000). Wnt signaling: an embarrassment of receptors. Current Biology, 10, R919–R922.PubMedGoogle Scholar
  4. 4.
    Mao, J., Wang, J., Liu, B., et al. (2001). Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Molecular Cell, 7, 801–809.PubMedGoogle Scholar
  5. 5.
    Hagen, T., Sethi, J. K., Foxwell, N., & Vidal-Puig, A. (2004). Signalling activity of beta-catenin targeted to different subcellular compartments. Biochemical Journal, 379, 471–477.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Papkoff, J., Rubinfeld, B., Schryver, B., & Polakis, P. (1996). Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. Molecular and Cellular Biology, 16, 2128–2134.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Papkoff, J., & Aikawa, M. (1998). WNT-1 and HGF regulate GSK3 beta activity and beta-catenin signaling in mammary epithelial cells. Biochemical and Biophysical Research Communications, 247, 851–858.PubMedGoogle Scholar
  8. 8.
    Archbold, H. C., Yang, Y. X., Chen, L., & Cadigan, K. M. (2011). How do they do Wnt they do?: regulation of transcription by the Wnt/beta-catenin pathway. Acta Physiologica (Oxford, England), 204, 74–109.Google Scholar
  9. 9.
    Teo, J. L., & Kahn, M. (2010). The Wnt signaling pathway in cellular proliferation and differentiation: a tale of two coactivators. Advanced Drug Delivery Reviews, 62, 1149–1155.PubMedGoogle Scholar
  10. 10.
    Sustmann, C., Flach, H., Ebert, H., Eastman, Q., & Grosschedl, R. (2008). Cell-type-specific function of BCL9 involves a transcriptional activation domain that synergizes with beta-catenin. Molecular and Cellular Biology, 28, 3526–3537.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Brantjes, H., Roose, J., van De Wetering, M., & Clevers, H. (2001). All Tcf HMG box transcription factors interact with Groucho-related co-repressors. Nucleic Acids Research, 29, 1410–1419.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Christian, J. L., Gavin, B. J., McMahon, A. P., & Moon, R. T. (1991). Isolation of cDNAs partially encoding four Xenopus Wnt-1/int-1-related proteins and characterization of their transient expression during embryonic development. Developmental Biology, 143, 230–234.PubMedGoogle Scholar
  13. 13.
    Moon, R. T., Campbell, R. M., Christian, J. L., McGrew, L. L., Shih, J., & Fraser, S. (1993). Xwnt-5A: a maternal Wnt that affects morphogenetic movements after overexpression in embryos of Xenopus laevis. Development, 119, 97–111.PubMedGoogle Scholar
  14. 14.
    Kohn, A. D., & Moon, R. T. (2005). Wnt and calcium signaling: beta-catenin-independent pathways. Cell Calcium, 38, 439–446.PubMedGoogle Scholar
  15. 15.
    Torres, M. A., Yang-Snyder, J. A., Purcell, S. M., DeMarais, A. A., McGrew, L. L., & Moon, R. T. (1996). Activities of the Wnt-1 class of secreted signaling factors are antagonized by the Wnt-5A class and by a dominant negative cadherin in early Xenopus development. Journal of Cell Biology, 133, 1123–1137.PubMedGoogle Scholar
  16. 16.
    Ahumada, A., Slusarski, D. C., Liu, X., Moon, R. T., Malbon, C. C., & Wang, H. Y. (2002). Signaling of rat Frizzled-2 through phosphodiesterase and cyclic GMP. Science, 298, 2006–2010.PubMedGoogle Scholar
  17. 17.
    Ma, L., & Wang, H. Y. (2007). Mitogen-activated protein kinase p38 regulates the Wnt/cyclic GMP/Ca2+ non-canonical pathway. Journal of Biological Chemistry, 282, 28980–28990.PubMedGoogle Scholar
  18. 18.
    Sheldahl, L. C., Slusarski, D. C., Pandur, P., Miller, J. R., Kuhl, M., & Moon, R. T. (2003). Dishevelled activates Ca2+ flux, PKC, and CamKII in vertebrate embryos. Journal of Cell Biology, 161, 769–777.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Schlessinger, K., McManus, E. J., & Hall, A. (2007). Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity. Journal of Cell Biology, 178, 355–361.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Sheldahl, L. C., Park, M., Malbon, C. C., & Moon, R. T. (1999). Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Current Biology, 9, 695–698.PubMedGoogle Scholar
  21. 21.
    Ishitani, T., Kishida, S., Hyodo-Miura, J., et al. (2003). The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. Molecular and Cellular Biology, 23, 131–139.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Kuhl, M., Sheldahl, L. C., Malbon, C. C., & Moon, R. T. (2000). Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus. Journal of Biological Chemistry, 275, 12701–12711.PubMedGoogle Scholar
  23. 23.
    Saneyoshi, T., Kume, S., Amasaki, Y., & Mikoshiba, K. (2002). The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos. Nature, 417, 295–299.PubMedGoogle Scholar
  24. 24.
    Hogan, P. G., Chen, L., Nardone, J., & Rao, A. (2003). Transcriptional regulation by calcium, calcineurin, and NFAT. Genes & Development, 17, 2205–2232.Google Scholar
  25. 25.
    Wang, Y., & Nathans, J. (2007). Tissue/planar cell polarity in vertebrates: new insights and new questions. Development, 134, 647–658.PubMedGoogle Scholar
  26. 26.
    Lee, H. K., & Deneen, B. (2012). Daam2 is required for dorsal patterning via modulation of canonical Wnt signaling in the developing spinal cord. Developmental Cell, 22, 183–196.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Nusse, R., & Varmus, H. E. (1992). Wnt genes. Cell, 69, 1073–1087.PubMedGoogle Scholar
  28. 28.
    Smolich, B. D., McMahon, J. A., McMahon, A. P., & Papkoff, J. (1993). Wnt family proteins are secreted and associated with the cell surface. Molecular Biology of the Cell, 4, 1267–1275.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Fung, Y. K., Shackleford, G. M., Brown, A. M., Sanders, G. S., & Varmus, H. E. (1985). Nucleotide sequence and expression in vitro of cDNA derived from mRNA of int-1, a provirally activated mouse mammary oncogene. Molecular and Cellular Biology, 5, 3337–3344.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Mason, J. O., Kitajewski, J., & Varmus, H. E. (1992). Mutational analysis of mouse Wnt-1 identifies two temperature-sensitive alleles and attributes of Wnt-1 protein essential for transformation of a mammary cell line. Molecular Biology of the Cell, 3, 521–533.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Miller, J. R. (2002). The Wnts. Genome Biology, 3, REVIEWS3001.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Willert, K., Brown, J. D., Danenberg, E., et al. (2003). Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature, 423, 448–452.PubMedGoogle Scholar
  33. 33.
    Bartscherer, K., Pelte, N., Ingelfinger, D., & Boutros, M. (2006). Secretion of Wnt ligands requires Evi, a conserved transmembrane protein. Cell, 125, 523–533.PubMedGoogle Scholar
  34. 34.
    Tanaka, K., Kitagawa, Y., & Kadowaki, T. (2002). Drosophila segment polarity gene product porcupine stimulates the posttranslational N-glycosylation of wingless in the endoplasmic reticulum. Journal of Biological Chemistry, 277, 12816–12823.PubMedGoogle Scholar
  35. 35.
    Reichsman, F., Smith, L., & Cumberledge, S. (1996). Glycosaminoglycans can modulate extracellular localization of the wingless protein and promote signal transduction. Journal of Cell Biology, 135, 819–827.PubMedGoogle Scholar
  36. 36.
    Nusse, R. (2008). Wnt signaling and stem cell control. Cell Research, 18, 523–527.PubMedGoogle Scholar
  37. 37.
    Polakis P. (2012). Wnt signaling in cancer. Cold Spring Harbor perspectives in biology;4.Google Scholar
  38. 38.
    He, X., Semenov, M., Tamai, K., & Zeng, X. (2004). LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development, 131, 1663–1677.PubMedGoogle Scholar
  39. 39.
    Herz, J., Chen, Y., Masiulis, I., & Zhou, L. (2009). Expanding functions of lipoprotein receptors. Journal of Lipid Research, 50(Suppl), S287–S292.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Mikels, A. J., & Nusse, R. (2006). Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biology, 4, e115.PubMedCentralPubMedGoogle Scholar
  41. 41.
    de Lau, W., Barker, N., Low, T. Y., et al. (2011). Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature, 476, 293–297.PubMedGoogle Scholar
  42. 42.
    Glinka, A., Dolde, C., Kirsch, N., et al. (2011). LGR4 and LGR5 are R-spondin receptors mediating Wnt/beta-catenin and Wnt/PCP signalling. EMBO Reports, 12, 1055–1061.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Hao, H. X., Xie, Y., Zhang, Y., et al. (2012). ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature, 485, 195–200.PubMedGoogle Scholar
  44. 44.
    Finch, P. W., He, X., Kelley, M. J., et al. (1997). Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action. Proceedings of the National Academy of Sciences of the United States of America, 94, 6770–6775.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Hsieh, J. C., Kodjabachian, L., Rebbert, M. L., et al. (1999). A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature, 398, 431–436.PubMedGoogle Scholar
  46. 46.
    Mao, B., & Niehrs, C. (2003). Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene, 302, 179–183.PubMedGoogle Scholar
  47. 47.
    Choi, H. Y., Dieckmann, M., Herz, J., & Niemeier, A. (2009). Lrp4, a novel receptor for Dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo. PLoS One, 4, e7930.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Li, X., Zhang, Y., Kang, H., et al. (2005). Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. Journal of Biological Chemistry, 280, 19883–19887.PubMedGoogle Scholar
  49. 49.
    Balemans, W., Piters, E., Cleiren, E., et al. (2008). The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. Calcified Tissue International, 82, 445–453.PubMedGoogle Scholar
  50. 50.
    Leupin, O., Piters, E., Halleux, C., et al. (2011). Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. Journal of Biological Chemistry, 286, 19489–19500.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Mokhtarzada, S., Yu, C., Brickenden, A., & Choy, W. Y. (2010). Structural characterization of partially disordered human Chibby: insights into its function in the Wnt-signaling pathway. Biochemistry, 50, 715–726.PubMedCentralGoogle Scholar
  52. 52.
    Takemaru, K., Yamaguchi, S., Lee, Y. S., Zhang, Y., Carthew, R. W., & Moon, R. T. (2003). Chibby, a nuclear beta-catenin-associated antagonist of the Wnt/Wingless pathway. Nature, 422, 905–909.PubMedGoogle Scholar
  53. 53.
    Li, F. Q., Mofunanya, A., Harris, K., & Takemaru, K. (2008). Chibby cooperates with 14-3-3 to regulate beta-catenin subcellular distribution and signaling activity. Journal of Cell Biology, 181, 1141–1154.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Tago, K., Nakamura, T., Nishita, M., et al. (2000). Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein. Genes & Development, 14, 1741–1749.Google Scholar
  55. 55.
    Daheron, L., Opitz, S. L., Zaehres, H., et al. (2004). LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells, 22, 770–778.PubMedGoogle Scholar
  56. 56.
    Boyer, L. A., Lee, T. I., Cole, M. F., et al. (2005). Core transcriptional regulatory circuitry in human embryonic stem cells. Cell, 122, 947–956.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Okoye, U. C., Malbon, C. C., & Wang, H. Y. (2008). Wnt and Frizzled RNA expression in human mesenchymal and embryonic (H7) stem cells. Journal of Molecular Signaling, 3, 16.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Huelsken, J., Vogel, R., Brinkmann, V., Erdmann, B., Birchmeier, C., & Birchmeier, W. (2000). Requirement for beta-catenin in anterior-posterior axis formation in mice. Journal of Cell Biology, 148, 567–578.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Liu, P., Wakamiya, M., Shea, M. J., Albrecht, U., Behringer, R. R., & Bradley, A. (1999). Requirement for Wnt3 in vertebrate axis formation. Nature Genetics, 22, 361–365.PubMedGoogle Scholar
  60. 60.
    Parr, B. A., & McMahon, A. P. (1995). Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb. Nature, 374, 350–353.PubMedGoogle Scholar
  61. 61.
    McMahon, A. P., Joyner, A. L., Bradley, A., & McMahon, J. A. (1992). The midbrain-hindbrain phenotype of Wnt-1-/Wnt-1- mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum. Cell, 69, 581–595.PubMedGoogle Scholar
  62. 62.
    Stark, K., Vainio, S., Vassileva, G., & McMahon, A. P. (1994). Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature, 372, 679–683.PubMedGoogle Scholar
  63. 63.
    Bradley, R. S., Cowin, P., & Brown, A. M. (1993). Expression of Wnt-1 in PC12 cells results in modulation of plakoglobin and E-cadherin and increased cellular adhesion. Journal of Cell Biology, 123, 1857–1865.PubMedGoogle Scholar
  64. 64.
    Christian, J. L., & Moon, R. T. (1993). Interactions between Xwnt-8 and Spemann organizer signaling pathways generate dorsoventral pattern in the embryonic mesoderm of Xenopus. Genes & Development, 7, 13–28.Google Scholar
  65. 65.
    Dierick, H. A., & Bejsovec, A. (1998). Functional analysis of Wingless reveals a link between intercellular ligand transport and dorsal-cell-specific signaling. Development, 125, 4729–4738.PubMedGoogle Scholar
  66. 66.
    Bone, H. K., Nelson, A. S., Goldring, C. E., Tosh, D., & Welham, M. J. (2011). A novel chemically directed route for the generation of definitive endoderm from human embryonic stem cells based on inhibition of GSK-3. Journal of Cell Science, 124, 1992–2000.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Davidson, K. C., Adams, A. M., Goodson, J. M., et al. (2012). Wnt/beta-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4. Proceedings of the National Academy of Sciences of the United States of America, 109, 4485–4490.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Sumi, T., Tsuneyoshi, N., Nakatsuji, N., & Suemori, H. (2008). Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/beta-catenin, Activin/Nodal and BMP signaling. Development, 135, 2969–2979.PubMedGoogle Scholar
  69. 69.
    Martin, B. L., & Kimelman, D. (2012). Canonical Wnt signaling dynamically controls multiple stem cell fate decisions during vertebrate body formation. Developmental Cell, 22, 223–232.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Sato, N., Meijer, L., Skaltsounis, L., Greengard, P., & Brivanlou, A. H. (2004). Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Medicine, 10, 55–63.PubMedGoogle Scholar
  71. 71.
    Anton, R., Kestler, H. A., & Kuhl, M. (2007). Beta-catenin signaling contributes to stemness and regulates early differentiation in murine embryonic stem cells. FEBS Letters, 581, 5247–5254.PubMedGoogle Scholar
  72. 72.
    Ogawa, K., Nishinakamura, R., Iwamatsu, Y., Shimosato, D., & Niwa, H. (2006). Synergistic action of Wnt and LIF in maintaining pluripotency of mouse ES cells. Biochemical and Biophysical Research Communications, 343, 159–166.PubMedGoogle Scholar
  73. 73.
    Sokol, S. Y. (2011). Maintaining embryonic stem cell pluripotency with Wnt signaling. Development, 138, 4341–4350.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Voskas, D., Ling, L. S., Woodgett, J. R. (2010). Does GSK-3 provide a shortcut for PI3K activation of Wnt signalling? F1000 biology reports;2:82.Google Scholar
  75. 75.
    Singh, A. M., Reynolds, D., Cliff, T., et al. (2012). Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell, 10, 312–326.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Vallier, L., Mendjan, S., Brown, S., et al. (2009). Activin/Nodal signalling maintains pluripotency by controlling Nanog expression. Development, 136, 1339–1349.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Xu, R. H., Sampsell-Barron, T. L., Gu, F., et al. (2008). NANOG is a direct target of TGFbeta/activin-mediated SMAD signaling in human ESCs. Cell Stem Cell, 3, 196–206.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Beattie, G. M., Lopez, A. D., Bucay, N., et al. (2005). Activin A maintains pluripotency of human embryonic stem cells in the absence of feeder layers. Stem Cells, 23, 489–495.PubMedGoogle Scholar
  79. 79.
    Dalton, S. (2013). Signaling networks in human pluripotent stem cells. Current Opinion in Cell Biology, 25, 241–246.PubMedCentralPubMedGoogle Scholar
  80. 80.
    Lin, Z., Gao, C., Ning, Y., He, X., Wu, W., & Chen, Y. G. (2008). The pseudoreceptor BMP and activin membrane-bound inhibitor positively modulates Wnt/beta-catenin signaling. Journal of Biological Chemistry, 283, 33053–33058.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Hasegawa, K., Yasuda, S. Y., Teo, J. L., et al. (2012). Wnt signaling orchestration with a small molecule DYRK inhibitor provides long-term xeno-free human pluripotent cell expansion. Stem Cells Translational Medicine, 1, 18–28.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Wend, P., Holland, J. D., Ziebold, U., & Birchmeier, W. (2010). Wnt signaling in stem and cancer stem cells. Seminars in Cell & Developmental Biology, 21, 855–863.Google Scholar
  83. 83.
    Emami, K. H., Nguyen, C., Ma, H., et al. (2004). A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proceedings of the National Academy of Sciences of the United States of America, 101, 12682–12687.PubMedCentralPubMedGoogle Scholar
  84. 84.
    Gang, E. J., Hsieh, Y. T., Pham, J., et al. (2013). Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene.Google Scholar
  85. 85.
    Owen, M., & Friedenstein, A. J. (1988). Stromal stem cells: marrow-derived osteogenic precursors. Ciba Foundation Symposium, 136, 42–60.PubMedGoogle Scholar
  86. 86.
    Wakitani, S., Saito, T., & Caplan, A. I. (1995). Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle & Nerve, 18, 1417–1426.Google Scholar
  87. 87.
    Caplan, A. I., & Bruder, S. P. (2001). Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends in Molecular Medicine, 7, 259–264.PubMedGoogle Scholar
  88. 88.
    Barrilleaux, B., Phinney, D. G., Prockop, D. J., & O’Connor, K. C. (2006). Review: ex vivo engineering of living tissues with adult stem cells. Tissue Engineering, 12, 3007–3019.PubMedGoogle Scholar
  89. 89.
    Prockop, D. J. (1997). Marrow stromal cells as stem cells for nonhematopoietic tissues. Science, 276, 71–74.PubMedGoogle Scholar
  90. 90.
    Etheridge, S. L., Spencer, G. J., Heath, D. J., & Genever, P. G. (2004). Expression profiling and functional analysis of wnt signaling mechanisms in mesenchymal stem cells. Stem Cells, 22, 849–860.PubMedGoogle Scholar
  91. 91.
    Liu, G., Vijayakumar, S., Grumolato, L., et al. (2009). Canonical Wnts function as potent regulators of osteogenesis by human mesenchymal stem cells. Journal of Cell Biology, 185, 67–75.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Rosen, E. D., & MacDougald, O. A. (2006). Adipocyte differentiation from the inside out. Nature Reviews Molecular Cell Biology, 7, 885–896.PubMedGoogle Scholar
  93. 93.
    Rosen, E. D., Walkey, C. J., Puigserver, P., & Spiegelman, B. M. (2000). Transcriptional regulation of adipogenesis. Genes & Development, 14, 1293–1307.Google Scholar
  94. 94.
    Ross, S. E., Hemati, N., Longo, K. A., et al. (2000). Inhibition of adipogenesis by Wnt signaling. Science, 289, 950–953.PubMedGoogle Scholar
  95. 95.
    Bennett, C. N., Ross, S. E., Longo, K. A., et al. (2002). Regulation of Wnt signaling during adipogenesis. Journal of Biological Chemistry, 277, 30998–31004.PubMedGoogle Scholar
  96. 96.
    Longo, K. A., Wright, W. S., Kang, S., et al. (2004). Wnt10b inhibits development of white and brown adipose tissues. Journal of Biological Chemistry, 279, 35503–35509.PubMedGoogle Scholar
  97. 97.
    Vertino, A. M., Taylor-Jones, J. M., Longo, K. A., et al. (2005). Wnt10b deficiency promotes coexpression of myogenic and adipogenic programs in myoblasts. Molecular Biology of the Cell, 16, 2039–2048.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Van Camp JK, B. S., Zegers, D., Verrijken, A., Van Gaal, L. F., & Van Hul, W. (2012). Genetic association between WNT10B polymorphisms and obesity in a Belgian case–control population is restricted to males. Molecular Genetics and Metabolism, 105, 489–493.PubMedGoogle Scholar
  99. 99.
    Shen, L., Glowacki, J., & Zhou, S. (2011). Inhibition of adipocytogenesis by canonical WNT signaling in human mesenchymal stem cells. Experimental Cell Research, 317, 1796–1803.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Ai, M., Holmen, S. L., Van Hul, W., Williams, B. O., & Warman, M. L. (2005). Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Molecular and Cellular Biology, 25, 4946–4955.PubMedCentralPubMedGoogle Scholar
  101. 101.
    Qiu, W., Andersen, T. E., Bollerslev, J., Mandrup, S., Abdallah, B. M., & Kassem, M. (2007). Patients with high bone mass phenotype exhibit enhanced osteoblast differentiation and inhibition of adipogenesis of human mesenchymal stem cells. Journal of Bone and Mineral Research, 22, 1720–1731.PubMedGoogle Scholar
  102. 102.
    Christodoulides, C., Laudes, M., Cawthorn, W. P., et al. (2006). The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis. Journal of Cell Science, 119, 2613–2620.PubMedGoogle Scholar
  103. 103.
    Schulte, D. M., Muller, N., Neumann, K., et al. (2012). Pro-inflammatory wnt5a and anti-inflammatory sFRP5 are differentially regulated by nutritional factors in obese human subjects. PLoS One, 7, e32437.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Hu, W., Li, L., Yang, M., et al. (2013). Circulating Sfrp5 is a signature of obesity-related metabolic disorders and is regulated by glucose and liraglutide in humans. The Journal of Clinical Endocrinology and Metabolism, 98, 290–298.PubMedGoogle Scholar
  105. 105.
    Hu, Z., Deng, H., Qu, H. (2013). Plasma SFRP5 levels are decreased in Chinese subjects with obesity and type 2 diabetes and negatively correlated with parameters of insulin resistance. Diabetes research and clinical practice.Google Scholar
  106. 106.
    Park, J. R., Jung, J. W., Lee, Y. S., & Kang, K. S. (2008). The roles of Wnt antagonists Dkk1 and sFRP4 during adipogenesis of human adipose tissue-derived mesenchymal stem cells. Cell Proliferation, 41, 859–874.PubMedGoogle Scholar
  107. 107.
    Okamura, M., Kudo, H., Wakabayashi, K., et al. (2009). COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis. Proceedings of the National Academy of Sciences of the United States of America, 106, 5819–5824.PubMedCentralPubMedGoogle Scholar
  108. 108.
    Takada, I., Suzawa, M., Matsumoto, K., & Kato, S. (2007). Suppression of PPAR transactivation switches cell fate of bone marrow stem cells from adipocytes into osteoblasts. Annals of the New York Academy of Sciences, 1116, 182–195.PubMedGoogle Scholar
  109. 109.
    Garlid, K. D., Jaburek, M., & Jezek, P. (1998). The mechanism of proton transport mediated by mitochondrial uncoupling proteins. FEBS Letters, 438, 10–14.PubMedGoogle Scholar
  110. 110.
    Timmons, J. A., Wennmalm, K., Larsson, O., et al. (2007). Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proceedings of the National Academy of Sciences of the United States of America, 104, 4401–4406.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Bennett, C. N., Longo, K. A., Wright, W. S., et al. (2005). Regulation of osteoblastogenesis and bone mass by Wnt10b. Proceedings of the National Academy of Sciences of the United States of America, 102, 3324–3329.PubMedCentralPubMedGoogle Scholar
  112. 112.
    Gong, Y., Slee, R. B., Fukai, N., et al. (2001). LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell, 107, 513–523.PubMedGoogle Scholar
  113. 113.
    Boyden, L. M., Mao, J., Belsky, J., et al. (2002). High bone density due to a mutation in LDL-receptor-related protein 5. The New England Journal of Medicine, 346, 1513–1521.PubMedGoogle Scholar
  114. 114.
    Little, R. D., Carulli, J. P., Del Mastro, R. G., et al. (2002). A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. American Journal of Human Genetics, 70, 11–19.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Van Wesenbeeck, L., Cleiren, E., Gram, J., et al. (2003). Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. American Journal of Human Genetics, 72, 763–771.PubMedCentralPubMedGoogle Scholar
  116. 116.
    Piters, E., Culha, C., Moester, M., et al. (2010). First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function. Human Mutation, 31, E1526–E1543.PubMedGoogle Scholar
  117. 117.
    Balemans, W., Ebeling, M., Patel, N., et al. (2001). Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Human Molecular Genetics, 10, 537–543.PubMedGoogle Scholar
  118. 118.
    Brunkow, M. E., Gardner, J. C., Van Ness, J., et al. (2001). Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. American Journal of Human Genetics, 68, 577–589.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Costa, A. G., & Bilezikian, J. P. (2012). Sclerostin: therapeutic horizons based upon its actions. Current Osteoporosis Reports, 10, 64–72.PubMedGoogle Scholar
  120. 120.
    Bodine, P. V., Zhao, W., Kharode, Y. P., et al. (2004). The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Molecular Endocrinology, 18, 1222–1237.PubMedGoogle Scholar
  121. 121.
    Morvan, F., Boulukos, K., Clement-Lacroix, P., et al. (2006). Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. Journal of Bone and Mineral Research, 21, 934–945.PubMedGoogle Scholar
  122. 122.
    Holmen, S. L., Zylstra, C. R., Mukherjee, A., et al. (2005). Essential role of beta-catenin in postnatal bone acquisition. Journal of Biological Chemistry, 280, 21162–21168.PubMedGoogle Scholar
  123. 123.
    Yan, Y., Tang, D., Chen, M., et al. (2009). Axin2 controls bone remodeling through the beta-catenin-BMP signaling pathway in adult mice. Journal of Cell Science, 122, 3566–3578.PubMedCentralPubMedGoogle Scholar
  124. 124.
    Baksh, D., & Tuan, R. S. (2007). Canonical and non-canonical Wnts differentially affect the development potential of primary isolate of human bone marrow mesenchymal stem cells. Journal of Cellular Physiology, 212, 817–826.PubMedGoogle Scholar
  125. 125.
    Van Camp, J. K., Beckers, S., Zegers, D., et al. (2013). Genetic association study of WNT10B polymorphisms with BMD and adiposity parameters in Danish and Belgian males. Endocrine.Google Scholar
  126. 126.
    Bennett, C. N., Ouyang, H., Ma, Y. L., et al. (2007). Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. Journal of Bone and Mineral Research, 22, 1924–1932.PubMedGoogle Scholar
  127. 127.
    Gaur, T., Lengner, C. J., Hovhannisyan, H., et al. (2005). Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. Journal of Biological Chemistry, 280, 33132–33140.PubMedGoogle Scholar
  128. 128.
    Kang, S., Bennett, C. N., Gerin, I., Rapp, L. A., Hankenson, K. D., & Macdougald, O. A. (2007). Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. Journal of Biological Chemistry, 282, 14515–14524.PubMedGoogle Scholar
  129. 129.
    Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L., & Karsenty, G. (1997). Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell, 89, 747–754.PubMedGoogle Scholar
  130. 130.
    Rodriguez-Carballo, E., Ulsamer, A., Susperregui, A. R., et al. (2011). Conserved regulatory motifs in osteogenic gene promoters integrate cooperative effects of canonical Wnt and BMP pathways. Journal of Bone and Mineral Research, 26, 718–729.PubMedGoogle Scholar
  131. 131.
    Liu, Y., Rubin, B., Bodine, P. V., & Billiard, J. (2008). Wnt5a induces homodimerization and activation of Ror2 receptor tyrosine kinase. Journal of Cellular Biochemistry, 105, 497–502.PubMedGoogle Scholar
  132. 132.
    Takada, I., Mihara, M., Suzawa, M., et al. (2007). A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nature Cell Biology, 9, 1273–1285.PubMedGoogle Scholar
  133. 133.
    Li, X., Liu, P., Liu, W., et al. (2005). Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nature Genetics, 37, 945–952.PubMedGoogle Scholar
  134. 134.
    Vaes, B. L., Dechering, K. J., van Someren, E. P., et al. (2005). Microarray analysis reveals expression regulation of Wnt antagonists in differentiating osteoblasts. Bone, 36, 803–811.PubMedGoogle Scholar
  135. 135.
    Sharma, A. R., Choi, B. S., Park, J. M., et al. (2013). Rspo 1 promotes osteoblast differentiation via Wnt signaling pathway. Indian Journal of Biochemistry & Biophysics, 50, 19–25.Google Scholar
  136. 136.
    Nam, J. S., Turcotte, T. J., Smith, P. F., Choi, S., & Yoon, J. K. (2006). Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate beta-catenin-dependent gene expression. Journal of Biological Chemistry, 281, 13247–13257.PubMedGoogle Scholar
  137. 137.
    Kim, K. A., Wagle, M., Tran, K., et al. (2008). R-Spondin family members regulate the Wnt pathway by a common mechanism. Molecular Biology of the Cell, 19, 2588–2596.PubMedCentralPubMedGoogle Scholar
  138. 138.
    Binnerts, M. E., Kim, K. A., Bright, J. M., et al. (2007). R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proceedings of the National Academy of Sciences of the United States of America, 104, 14700–14705.PubMedCentralPubMedGoogle Scholar
  139. 139.
    Abed, E., Chan, T. F., Delalandre, A., Martel-Pelletier, J., Pelletier, J. P., & Lajeunesse, D. (2011). R-spondins are newly recognized players in osteoarthritis that regulate Wnt signaling in osteoblasts. Arthritis and Rheumatism, 63, 3865–3875.PubMedGoogle Scholar
  140. 140.
    Bi, W., Deng, J. M., Zhang, Z., Behringer, R. R., & de Crombrugghe, B. (1999). Sox9 is required for cartilage formation. Nature Genetics, 22, 85–89.PubMedGoogle Scholar
  141. 141.
    Luo, S., Shi, Q., Zha, Z., et al. (2013). Inactivation of Wnt/beta-catenin signaling in human adipose-derived stem cells is necessary for chondrogenic differentiation and maintenance. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.Google Scholar
  142. 142.
    von Maltzahn, J., Chang, N. C., Bentzinger, C. F., & Rudnicki, M. A. (2012). Wnt signaling in myogenesis. Trends in Cell Biology, 22, 602–609.Google Scholar
  143. 143.
    Shang, Y., Zhang, C., Wang, S., et al. (2007). Activated beta-catenin induces myogenesis and inhibits adipogenesis in BM-derived mesenchymal stromal cells. Cytotherapy, 9, 667–681.PubMedGoogle Scholar
  144. 144.
    Brack, A. S., Conboy, I. M., Conboy, M. J., Shen, J., & Rando, T. A. (2008). A temporal switch from notch to Wnt signaling in muscle stem cells is necessary for normal adult myogenesis. Cell Stem Cell, 2, 50–59.PubMedGoogle Scholar
  145. 145.
    Le Grand, F., Jones, A. E., Seale, V., Scime, A., & Rudnicki, M. A. (2009). Wnt7a activates the planar cell polarity pathway to drive the symmetric expansion of satellite stem cells. Cell Stem Cell, 4, 535–547.PubMedCentralPubMedGoogle Scholar
  146. 146.
    von Maltzahn, J., Bentzinger, C. F., & Rudnicki, M. A. (2012). Wnt7a-Fzd7 signalling directly activates the Akt/mTOR anabolic growth pathway in skeletal muscle. Nature Cell Biology, 14, 186–191.Google Scholar
  147. 147.
    Van Den Berg, D. J., Sharma, A. K., Bruno, E., & Hoffman, R. (1998). Role of members of the Wnt gene family in human hematopoiesis. Blood, 92, 3189–3202.Google Scholar
  148. 148.
    Reya, T., Duncan, A. W., Ailles, L., et al. (2003). A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature, 423, 409–414.PubMedGoogle Scholar
  149. 149.
    Fleming, H. E., Janzen, V., Lo Celso, C., et al. (2008). Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell, 2, 274–283.PubMedCentralPubMedGoogle Scholar
  150. 150.
    Nemeth, M. J., Topol, L., Anderson, S. M., Yang, Y., & Bodine, D. M. (2007). Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation. Proceedings of the National Academy of Sciences of the United States of America, 104, 15436–15441.PubMedCentralPubMedGoogle Scholar
  151. 151.
    Louis, I., Heinonen, K. M., Chagraoui, J., Vainio, S., Sauvageau, G., & Perreault, C. (2008). The signaling protein Wnt4 enhances thymopoiesis and expands multipotent hematopoietic progenitors through beta-catenin-independent signaling. Immunity, 29, 57–67.PubMedGoogle Scholar
  152. 152.
    Fevr, T., Robine, S., Louvard, D., & Huelsken, J. (2007). Wnt/beta-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Molecular and Cellular Biology, 27, 7551–7559.PubMedCentralPubMedGoogle Scholar
  153. 153.
    Pinto, D., Gregorieff, A., Begthel, H., & Clevers, H. (2003). Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes & Development, 17, 1709–1713.Google Scholar
  154. 154.
    Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell, 127, 469–480.PubMedGoogle Scholar
  155. 155.
    Schepers, A., & Clevers, H. (2012). Wnt signaling, stem cells, and cancer of the gastrointestinal tract. Cold Spring Harbor Perspectives in Biology, 4, a007989.PubMedCentralPubMedGoogle Scholar
  156. 156.
    Kongkanuntn, R., Bubb, V. J., Sansom, O. J., Wyllie, A. H., Harrison, D. J., & Clarke, A. R. (1999). Dysregulated expression of beta-catenin marks early neoplastic change in Apc mutant mice, but not all lesions arising in Msh2 deficient mice. Oncogene, 18, 7219–7225.PubMedGoogle Scholar
  157. 157.
    Kosinski, C., Li, V. S., Chan, A. S., et al. (2007). Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proceedings of the National Academy of Sciences of the United States of America, 104, 15418–15423.PubMedCentralPubMedGoogle Scholar
  158. 158.
    Korinek, V., Barker, N., Moerer, P., et al. (1998). Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genetics, 19, 379–383.PubMedGoogle Scholar
  159. 159.
    Hsu, S. Y., Liang, S. G., & Hsueh, A. J. (1998). Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Molecular Endocrinology, 12, 1830–1845.PubMedGoogle Scholar
  160. 160.
    Kim, K. A., Kakitani, M., Zhao, J., et al. (2005). Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science, 309, 1256–1259.PubMedGoogle Scholar
  161. 161.
    Andreu, P., Colnot, S., Godard, C., et al. (2005). Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine. Development, 132, 1443–1451.PubMedGoogle Scholar
  162. 162.
    Andreu, P., Peignon, G., Slomianny, C., et al. (2008). A genetic study of the role of the Wnt/beta-catenin signalling in Paneth cell differentiation. Developmental Biology, 324, 288–296.PubMedGoogle Scholar
  163. 163.
    Sato, T., van Es, J. H., Snippert, H. J., et al. (2011). Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature, 469, 415–418.PubMedCentralPubMedGoogle Scholar
  164. 164.
    Barker, N., Huch, M., Kujala, P., et al. (2010). Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell, 6, 25–36.PubMedGoogle Scholar
  165. 165.
    McDonald, S. A., Greaves, L. C., Gutierrez-Gonzalez, L., et al. (2008). Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology, 134, 500–510.PubMedGoogle Scholar
  166. 166.
    Lim, X., Nusse, R. (2013). Wnt signaling in skin development, homeostasis, and disease. Cold Spring Harbor perspectives in biology;5.Google Scholar
  167. 167.
    Ohyama, M., Terunuma, A., Tock, C. L., et al. (2006). Characterization and isolation of stem cell-enriched human hair follicle bulge cells. Journal of Clinical Investigation, 116, 249–260.PubMedCentralPubMedGoogle Scholar
  168. 168.
    Gat, U., DasGupta, R., Degenstein, L., & Fuchs, E. (1998). De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell, 95, 605–614.PubMedGoogle Scholar
  169. 169.
    Tumbar, T., Guasch, G., Greco, V., et al. (2004). Defining the epithelial stem cell niche in skin. Science, 303, 359–363.PubMedCentralPubMedGoogle Scholar
  170. 170.
    Jaks, V., Barker, N., Kasper, M., et al. (2008). Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nature Genetics, 40, 1291–1299.PubMedGoogle Scholar
  171. 171.
    Deome, K. B., Faulkin, L. J., Jr., Bern, H. A., & Blair, P. B. (1959). Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Research, 19, 515–520.PubMedGoogle Scholar
  172. 172.
    Young, L. J., Medina, D., DeOme, K. B., & Daniel, C. W. (1971). The influence of host and tissue age on life span and growth rate of serially transplanted mouse mammary gland. Experimental Gerontology, 6, 49–56.PubMedGoogle Scholar
  173. 173.
    Zeng, Y. A., & Nusse, R. (2010). Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell, 6, 568–577.PubMedCentralPubMedGoogle Scholar
  174. 174.
    Lindvall, C., Evans, N. C., Zylstra, C. R., Li, Y., Alexander, C. M., & Williams, B. O. (2006). The Wnt signaling receptor Lrp5 is required for mammary ductal stem cell activity and Wnt1-induced tumorigenesis. Journal of Biological Chemistry, 281, 35081–35087.PubMedGoogle Scholar
  175. 175.
    Lindvall, C., Zylstra, C. R., Evans, N., et al. (2009). The Wnt co-receptor Lrp6 is required for normal mouse mammary gland development. PLoS One, 4, e5813.PubMedCentralPubMedGoogle Scholar
  176. 176.
    Lee, S. M., Tole, S., Grove, E., & McMahon, A. P. (2000). A local Wnt-3a signal is required for development of the mammalian hippocampus. Development, 127, 457–467.PubMedGoogle Scholar
  177. 177.
    Lie, D. C., Colamarino, S. A., Song, H. J., et al. (2005). Wnt signalling regulates adult hippocampal neurogenesis. Nature, 437, 1370–1375.PubMedGoogle Scholar
  178. 178.
    Gunhaga, L., Marklund, M., Sjodal, M., Hsieh, J. C., Jessell, T. M., & Edlund, T. (2003). Specification of dorsal telencephalic character by sequential Wnt and FGF signaling. Nature Neuroscience, 6, 701–707.PubMedGoogle Scholar
  179. 179.
    Wisniewska, M. B., Misztal, K., Michowski, W., et al. (2010). LEF1/beta-catenin complex regulates transcription of the Cav3.1 calcium channel gene (Cacna1g) in thalamic neurons of the adult brain. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 30, 4957–4969.Google Scholar
  180. 180.
    Shimogori, T., VanSant, J., Paik, E., & Grove, E. A. (2004). Members of the Wnt, Fz, and Frp gene families expressed in postnatal mouse cerebral cortex. The Journal of Comparative Neurology, 473, 496–510.PubMedGoogle Scholar
  181. 181.
    Qu, Q., Sun, G., Li, W., et al. (2010). Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal. Nature Cell Biology, 12, 31–40. sup pp 1-9.PubMedCentralPubMedGoogle Scholar
  182. 182.
    Yu, J. M., Kim, J. H., Song, G. S., & Jung, J. S. (2006). Increase in proliferation and differentiation of neural progenitor cells isolated from postnatal and adult mice brain by Wnt-3a and Wnt-5a. Molecular and Cellular Biochemistry, 288, 17–28.PubMedGoogle Scholar
  183. 183.
    Lu, W., Yamamoto, V., Ortega, B., & Baltimore, D. (2004). Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell, 119, 97–108.PubMedGoogle Scholar
  184. 184.
    Patthy, L. (2000). The WIF, module. Trends in Biochemical Sciences, 25, 12–13.PubMedGoogle Scholar
  185. 185.
    Adachi, K., Mirzadeh, Z., Sakaguchi, M., et al. (2007). Beta-catenin signaling promotes proliferation of progenitor cells in the adult mouse subventricular zone. Stem Cells, 25, 2827–2836.PubMedGoogle Scholar
  186. 186.
    Marinaro, C., Pannese, M., Weinandy, F., et al. (2012). Wnt signaling has opposing roles in the developing and the adult brain that are modulated by Hipk1. Cerebral Cortex, 22, 2415–2427.PubMedGoogle Scholar
  187. 187.
    Wisniewska, M. B. (2013). Physiological role of beta-catenin/TCF signaling in neurons of the adult brain. Neurochemical Research, 38, 1144–1155.PubMedCentralPubMedGoogle Scholar
  188. 188.
    Marui, T., Funatogawa, I., Koishi, S., et al. (2010). Association between autism and variants in the wingless-type MMTV integration site family member 2 (WNT2) gene. International Journal of Neuropsychopharmacology, 13, 443–449.PubMedGoogle Scholar
  189. 189.
    Wassink, T. H., Piven, J., Vieland, V. J., et al. (2001). Evidence supporting WNT2 as an autism susceptibility gene. American Journal of Medical Genetics, 105, 406–413.PubMedGoogle Scholar
  190. 190.
    Kishimoto, M., Ujike, H., Okahisa, Y., et al. (2008). The Frizzled 3 gene is associated with methamphetamine psychosis in the Japanese population. Behavioral and Brain Functions: BBF, 4, 37.PubMedCentralPubMedGoogle Scholar
  191. 191.
    Yang, J., Si, T., Ling, Y., et al. (2003). Association study of the human FZD3 locus with schizophrenia. Biological Psychiatry, 54, 1298–1301.PubMedGoogle Scholar
  192. 192.
    Alkelai, A., Greenbaum, L., Lupoli, S., et al. (2012). Association of the type 2 diabetes mellitus susceptibility gene, TCF7L2, with schizophrenia in an Arab-Israeli family sample. PLoS One, 7, e29228.PubMedCentralPubMedGoogle Scholar
  193. 193.
    Hansen, T., Ingason, A., Djurovic, S., et al. (2011). At-risk variant in TCF7L2 for type II diabetes increases risk of schizophrenia. Biological Psychiatry, 70, 59–63.PubMedGoogle Scholar
  194. 194.
    Proitsi, P., Li, T., Hamilton, G., et al. (2008). Positional pathway screen of wnt signaling genes in schizophrenia: association with DKK4. Biological Psychiatry, 63, 13–16.PubMedGoogle Scholar
  195. 195.
    Cui, D. H., Jiang, K. D., Jiang, S. D., Xu, Y. F., & Yao, H. (2005). The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia. Molecular Psychiatry, 10, 669–677.PubMedGoogle Scholar
  196. 196.
    Dickins, E. M., & Salinas, P. C. (2013). Wnts in action: from synapse formation to synaptic maintenance. Frontiers in Cellular Neuroscience, 7, 162.PubMedCentralPubMedGoogle Scholar
  197. 197.
    Caricasole, A., Copani, A., Caraci, F., et al. (2004). Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer’s brain. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 24, 6021–6027.Google Scholar
  198. 198.
    Purro, S. A., Dickins, E. M., & Salinas, P. C. (2012). The secreted Wnt antagonist Dickkopf-1 is required for amyloid beta-mediated synaptic loss. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 32, 3492–3498.Google Scholar
  199. 199.
    Lathia, J. D., Gallagher, J., Myers, J. T., et al. (2011). Direct in vivo evidence for tumor propagation by glioblastoma cancer stem cells. PLoS One, 6, e24807.PubMedCentralPubMedGoogle Scholar
  200. 200.
    Clarke, M. F., Dick, J. E., Dirks, P. B., et al. (2006). Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Research, 66, 9339–9344.PubMedGoogle Scholar
  201. 201.
    Assou, S., Le Carrour, T., Tondeur, S., et al. (2007). A meta-analysis of human embryonic stem cells transcriptome integrated into a web-based expression atlas. Stem Cells, 25, 961–973.PubMedCentralPubMedGoogle Scholar
  202. 202.
    Ben-Porath, I., Thomson, M. W., Carey, V. J., et al. (2008). An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nature Genetics, 40, 499–507.PubMedCentralPubMedGoogle Scholar
  203. 203.
    LaBarge, M. A. (2010). The difficulty of targeting cancer stem cell niches. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 16, 3121–3129.Google Scholar
  204. 204.
    Shtutman, M., Zhurinsky, J., Simcha, I., et al. (1999). The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proceedings of the National Academy of Sciences of the United States of America, 96, 5522–5527.PubMedCentralPubMedGoogle Scholar
  205. 205.
    He, T. C., Sparks, A. B., Rago, C., et al. (1998). Identification of c-MYC as a target of the APC pathway. Science, 281, 1509–1512.PubMedGoogle Scholar
  206. 206.
    Mizutani, K., Miyamoto, S., Nagahata, T., Konishi, N., Emi, M., & Onda, M. (2005). Upregulation and overexpression of DVL1, the human counterpart of the Drosophila dishevelled gene, in prostate cancer. Tumori, 91, 546–551.PubMedGoogle Scholar
  207. 207.
    Uematsu, K., He, B., You, L., Xu, Z., McCormick, F., & Jablons, D. M. (2003). Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. Oncogene, 22, 7218–7221.PubMedGoogle Scholar
  208. 208.
    Uematsu, K., Kanazawa, S., You, L., et al. (2003). Wnt pathway activation in mesothelioma: evidence of Dishevelled overexpression and transcriptional activity of beta-catenin. Cancer Research, 63, 4547–4551.PubMedGoogle Scholar
  209. 209.
    Eyler, C. E., & Rich, J. N. (2008). Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 26, 2839–2845.Google Scholar
  210. 210.
    Koch, U., Krause, M., & Baumann, M. (2010). Cancer stem cells at the crossroads of current cancer therapy failures–radiation oncology perspective. Seminars in Cancer Biology, 20, 116–124.PubMedGoogle Scholar
  211. 211.
    Reyes, M., & Verfaillie, C. M. (2001). Characterization of multipotent adult progenitor cells, a subpopulation of mesenchymal stem cells. Annals of the New York Academy of Sciences, 938, 231–233. discussion 3-5.PubMedGoogle Scholar
  212. 212.
    Zuk, P. A., Zhu, M., Ashjian, P., et al. (2002). Human adipose tissue is a source of multipotent stem cells. Molecular Biology of the Cell, 13, 4279–4295.PubMedCentralPubMedGoogle Scholar
  213. 213.
    Kohler, T., Plettig, R., Wetzstein, W., et al. (1999). Defining optimum conditions for the ex vivo expansion of human umbilical cord blood cells. Influences of progenitor enrichment, interference with feeder layers, early-acting cytokines and agitation of culture vessels. Stem Cells, 17, 19–24.PubMedGoogle Scholar
  214. 214.
    Nolta, J. A., Thiemann, F. T., Arakawa-Hoyt, J., et al. (2002). The AFT024 stromal cell line supports long-term ex vivo maintenance of engrafting multipotent human hematopoietic progenitors. Leukemia, 16, 352–361.PubMedGoogle Scholar
  215. 215.
    O’Connor, K. C., Song, H., Rosenzweig, N., & Jansen, D. A. (2003). Extracellular matrix substrata alter adipocyte yield and lipogenesis in primary cultures of stromal-vascular cells from human adipose. Biotechnology Letters, 25, 1967–1972.PubMedGoogle Scholar
  216. 216.
    Koller, M. R., Bender, J. G., Papoutsakis, E. T., & Miller, W. M. (1992). Beneficial effects of reduced oxygen tension and perfusion in long-term hematopoietic cultures. Annals of the New York Academy of Sciences, 665, 105–116.PubMedGoogle Scholar
  217. 217.
    Green, D., Howard, D., Yang, X., Kelly, M., & Oreffo, R. O. (2003). Natural marine sponge fiber skeleton: a biomimetic scaffold for human osteoprogenitor cell attachment, growth, and differentiation. Tissue Engineering, 9, 1159–1166.PubMedGoogle Scholar
  218. 218.
    Hong, L., Peptan, I., Clark, P., & Mao, J. J. (2005). Ex vivo adipose tissue engineering by human marrow stromal cell seeded gelatin sponge. Annals of Biomedical Engineering, 33, 511–517.PubMedGoogle Scholar
  219. 219.
    Sato, T., & Clevers, H. (2013). Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science, 340, 1190–1194.PubMedGoogle Scholar
  220. 220.
    Gazit, A., Yaniv, A., Bafico, A., et al. (1999). Human frizzled 1 interacts with transforming Wnts to transduce a TCF dependent transcriptional response. Oncogene, 18, 5959–5966.PubMedGoogle Scholar
  221. 221.
    Spinsanti, P., De Vita, T., Caruso, A., et al. (2008). Differential activation of the calcium/protein kinase C and the canonical beta-catenin pathway by Wnt1 and Wnt7a produces opposite effects on cell proliferation in PC12 cells. Journal of Neurochemistry, 104, 1588–1598.PubMedGoogle Scholar
  222. 222.
    Castelo-Branco, G., Wagner, J., Rodriguez, F. J., et al. (2003). Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. Proceedings of the National Academy of Sciences of the United States of America, 100, 12747–12752.PubMedCentralPubMedGoogle Scholar
  223. 223.
    Rebhan, M., Chalifa-Caspi, V., Prilusky, J., & Lancet, D. (1997). GeneCards: integrating information about genes, proteins and diseases. Trends in Genetics: TIG, 13, 163.PubMedGoogle Scholar
  224. 224.
    Yanai, I., Benjamin, H., Shmoish, M., et al. (2005). Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification. Bioinformatics, 21, 650–659.PubMedGoogle Scholar
  225. 225.
    Gene Cards. (Accessed 31 August, 2013, at
  226. 226.
    McMahon, A. P., & Bradley, A. (1990). The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell, 62, 1073–1085.PubMedGoogle Scholar
  227. 227.
    Thomas, K. R., & Capecchi, M. R. (1990). Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development. Nature, 346, 847–850.PubMedGoogle Scholar
  228. 228.
    Laine, C. M., Joeng, K. S., Campeau, P. M., et al. (2013). WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. The New England Journal of Medicine, 368, 1809–1816.PubMedCentralPubMedGoogle Scholar
  229. 229.
    Karasawa, T., Yokokura, H., Kitajewski, J., & Lombroso, P. J. (2002). Frizzled-9 is activated by Wnt-2 and functions in Wnt/beta -catenin signaling. Journal of Biological Chemistry, 277, 37479–37486.PubMedGoogle Scholar
  230. 230.
    Sousa, K. M., Villaescusa, J. C., Cajanek, L., et al. (2010). Wnt2 regulates progenitor proliferation in the developing ventral midbrain. Journal of Biological Chemistry, 285, 7246–7253.PubMedCentralPubMedGoogle Scholar
  231. 231.
    Wainwright, B. J., Scambler, P. J., Stanier, P., et al. (1988). Isolation of a human gene with protein sequence similarity to human and murine int-1 and the Drosophila segment polarity mutant wingless. The EMBO Journal, 7, 1743–1748.PubMedCentralPubMedGoogle Scholar
  232. 232.
    Huguet, E. L., McMahon, J. A., McMahon, A. P., Bicknell, R., & Harris, A. L. (1994). 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 Research, 54, 2615–2621.PubMedGoogle Scholar
  233. 233.
    Goss, A. M., Tian, Y., Tsukiyama, T., et al. (2009). Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. Developmental Cell, 17, 290–298.PubMedCentralPubMedGoogle Scholar
  234. 234.
    Monkley, S. J., Delaney, S. J., Pennisi, D. J., Christiansen, J. H., & Wainwright, B. J. (1996). Targeted disruption of the Wnt2 gene results in placentation defects. Development, 122, 3343–3353.PubMedGoogle Scholar
  235. 235.
    Katoh, M., Kirikoshi, H., Terasaki, H., & Shiokawa, K. (2001). WNT2B2 mRNA, up-regulated in primary gastric cancer, is a positive regulator of the WNT- beta-catenin-TCF signaling pathway. Biochemical and Biophysical Research Communications, 289, 1093–1098.PubMedGoogle Scholar
  236. 236.
    Bergstein, I., Eisenberg, L. M., Bhalerao, J., et al. (1997). Isolation of two novel WNT genes, WNT14 and WNT15, one of which (WNT15) is closely linked to WNT3 on human chromosome 17q21. Genomics, 46, 450–458.PubMedGoogle Scholar
  237. 237.
    Katoh, M., Hirai, M., Sugimura, T., & Terada, M. (1996). Cloning, expression and chromosomal localization of Wnt-13, a novel member of the Wnt gene family. Oncogene, 13, 873–876.PubMedGoogle Scholar
  238. 238.
    Kim, M., Lee, H. C., Tsedensodnom, O., et al. (2008). Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/beta-catenin signaling pathway in hepatocellular carcinoma cells. Journal of Hepatology, 48, 780–791.PubMedCentralPubMedGoogle Scholar
  239. 239.
    Kobune, M., Chiba, H., Kato, J., et al. (2007). Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism. Molecular Cancer Therapeutics, 6, 1774–1784.PubMedGoogle Scholar
  240. 240.
    Niemann, S., Zhao, C., Pascu, F., et al. (2004). Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. American Journal of Human Genetics, 74, 558–563.PubMedCentralPubMedGoogle Scholar
  241. 241.
    Verkaar, F., van Rosmalen, J. W., Smits, J. F., Blankesteijn, W. M., & Zaman, G. J. (2009). Stably overexpressed human Frizzled-2 signals through the beta-catenin pathway and does not activate Ca2+ -mobilization in Human Embryonic Kidney 293 cells. Cellular Signalling, 21, 22–33.PubMedGoogle Scholar
  242. 242.
    Carmon, K. S., & Loose, D. S. (2010). Development of a bioassay for detection of Wnt-binding affinities for individual frizzled receptors. Analytical Biochemistry, 401, 288–294.PubMedCentralPubMedGoogle Scholar
  243. 243.
    Qiu, W., Chen, L., & Kassem, M. (2011). Activation of non-canonical Wnt/JNK pathway by Wnt3a is associated with differentiation fate determination of human bone marrow stromal (mesenchymal) stem cells. Biochemical and Biophysical Research Communications, 413, 98–104.PubMedGoogle Scholar
  244. 244.
    Qu, F., Wang, J., Xu, N., et al. (2013). WNT3A modulates chondrogenesis via canonical and non-canonical Wnt pathways in MSCs. Front Bioscience (Landmark Ed), 18, 493–503.Google Scholar
  245. 245.
    Steele, B. M., Harper, M. T., Smolenski, A. P., et al. (2012). WNT-3a modulates platelet function by regulating small GTPase activity. FEBS Letters, 586, 2267–2272.PubMedGoogle Scholar
  246. 246.
    Hubner, R., Schmole, A. C., Liedmann, A., Frech, M. J., Rolfs, A., & Luo, J. (2010). Differentiation of human neural progenitor cells regulated by Wnt-3a. Biochemical and Biophysical Research Communications, 400, 358–362.PubMedGoogle Scholar
  247. 247.
    Hay, D. C., Fletcher, J., Payne, C., et al. (2008). Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proceedings of the National Academy of Sciences of the United States of America, 105, 12301–12306.PubMedCentralPubMedGoogle Scholar
  248. 248.
    Tran, T. H., Wang, X., Browne, C., et al. (2009). Wnt3a-induced mesoderm formation and cardiomyogenesis in human embryonic stem cells. Stem Cells, 27, 1869–1878.PubMedGoogle Scholar
  249. 249.
    Saitoh, T., Hirai, M., & Katoh, M. (2001). Molecular cloning and characterization of WNT3A and WNT14 clustered in human chromosome 1q42 region. Biochemical and Biophysical Research Communications, 284, 1168–1175.PubMedGoogle Scholar
  250. 250.
    Takada, S., Stark, K. L., Shea, M. J., Vassileva, G., McMahon, J. A., & McMahon, A. P. (1994). Wnt-3a regulates somite and tailbud formation in the mouse embryo. Genes & Development, 8, 174–189.Google Scholar
  251. 251.
    Biason-Lauber, A., Konrad, D., Navratil, F., & Schoenle, E. J. (2004). A WNT4 mutation associated with Mullerian-duct regression and virilization in a 46, XX woman. The New England Journal Of Medicine, 351, 792–798.PubMedGoogle Scholar
  252. 252.
    Vainio, S., Heikkila, M., Kispert, A., Chin, N., & McMahon, A. P. (1999). Female development in mammals is regulated by Wnt-4 signalling. Nature, 397, 405–409.PubMedGoogle Scholar
  253. 253.
    Jeays-Ward, K., Dandonneau, M., & Swain, A. (2004). Wnt4 is required for proper male as well as female sexual development. Developmental Biology, 276, 431–440.PubMedGoogle Scholar
  254. 254.
    Shan, J., Jokela, T., Peltoketo, H., & Vainio, S. (2009). Generation of an allele to inactivate Wnt4 gene function conditionally in the mouse. Genesis, 47, 782–788.PubMedGoogle Scholar
  255. 255.
    Mandel, H., Shemer, R., Borochowitz, Z. U., et al. (2008). SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4. American Journal of Human Genetics, 82, 39–47.PubMedCentralPubMedGoogle Scholar
  256. 256.
    Vivante, A., Mark-Danieli, M., Davidovits, M., et al. (2013). Renal hypodysplasia associates with a WNT4 variant that causes aberrant canonical WNT signaling. Journal of the American Society of Nephrology : JASN, 24, 550–558.PubMedCentralPubMedGoogle Scholar
  257. 257.
    Bazhin, A. V., Tambor, V., Dikov, B., Philippov, P. P., Schadendorf, D., & Eichmuller, S. B. (2010). cGMP-phosphodiesterase 6, transducin and Wnt5a/Frizzled-2-signaling control cGMP and Ca(2+) homeostasis in melanoma cells. Cellular and Molecular Life Sciences: CMLS, 67, 817–828.PubMedGoogle Scholar
  258. 258.
    Kawasaki, A., Torii, K., Yamashita, Y., et al. (2007). Wnt5a promotes adhesion of human dermal fibroblasts by triggering a phosphatidylinositol-3 kinase/Akt signal. Cellular Signalling, 19, 2498–2506.PubMedGoogle Scholar
  259. 259.
    He, X., Saint-Jeannet, J. P., Wang, Y., Nathans, J., Dawid, I., & Varmus, H. (1997). A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science, 275, 1652–1654.PubMedGoogle Scholar
  260. 260.
    Oishi, I., Suzuki, H., Onishi, N., et al. (2003). The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes to Cells: Devoted to Molecular & Cellular Mechanisms, 8, 645–654.Google Scholar
  261. 261.
    Weeraratna, A. T., Jiang, Y., Hostetter, G., et al. (2002). Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell, 1, 279–288.PubMedGoogle Scholar
  262. 262.
    Schulte, G., Bryja, V., Rawal, N., Castelo-Branco, G., Sousa, K. M., & Arenas, E. (2005). Purified Wnt-5a increases differentiation of midbrain dopaminergic cells and dishevelled phosphorylation. Journal of Neurochemistry, 92, 1550–1553.PubMedGoogle Scholar
  263. 263.
    Santos, A., Bakker, A. D., de Blieck-Hogervorst, J. M., & Klein-Nulend, J. (2010). WNT5A induces osteogenic differentiation of human adipose stem cells via rho-associated kinase ROCK. Cytotherapy, 12, 924–932.PubMedGoogle Scholar
  264. 264.
    Roarty, K., & Serra, R. (2007). Wnt5a is required for proper mammary gland development and TGF-beta-mediated inhibition of ductal growth. Development, 134, 3929–3939.PubMedGoogle Scholar
  265. 265.
    Hwang, Y. S., Chung, B. G., Ortmann, D., Hattori, N., Moeller, H. C., & Khademhosseini, A. (2009). Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11. Proceedings of the National Academy of Sciences of the United States of America, 106, 16978–16983.PubMedCentralPubMedGoogle Scholar
  266. 266.
    Clark, C. C., Cohen, I., Eichstetter, I., et al. (1993). Molecular cloning of the human proto-oncogene Wnt-5A and mapping of the gene (WNT5A) to chromosome 3p14-p21. Genomics, 18, 249–260.PubMedGoogle Scholar
  267. 267.
    Yamaguchi, T. P., Bradley, A., McMahon, A. P., & Jones, S. (1999). A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development, 126, 1211–1223.PubMedGoogle Scholar
  268. 268.
    Person, A. D., Beiraghi, S., Sieben, C. M., et al. (2010). WNT5A mutations in patients with autosomal dominant Robinow syndrome. Developmental Dynamics: An Official Publication of the American Association of Anatomists, 239, 327–337.Google Scholar
  269. 269.
    Morioka, K., Tanikawa, C., Ochi, K., et al. (2009). Orphan receptor tyrosine kinase ROR2 as a potential therapeutic target for osteosarcoma. Cancer Science, 100, 1227–1233.PubMedGoogle Scholar
  270. 270.
    Bradley, E. W., & Drissi, M. H. (2011). Wnt5b regulates mesenchymal cell aggregation and chondrocyte differentiation through the planar cell polarity pathway. Journal of Cellular Physiology, 226, 1683–1693.PubMedGoogle Scholar
  271. 271.
    Kanazawa, A., Tsukada, S., Kamiyama, M., Yanagimoto, T., Nakajima, M., & Maeda, S. (2005). Wnt5b partially inhibits canonical Wnt/beta-catenin signaling pathway and promotes adipogenesis in 3T3-L1 preadipocytes. Biochemical and Biophysical Research Communications, 330, 505–510.PubMedGoogle Scholar
  272. 272.
    van Tienen, F. H., Laeremans, H., van der Kallen, C. J., & Smeets, H. J. (2009). Wnt5b stimulates adipogenesis by activating PPARgamma, and inhibiting the beta-catenin dependent Wnt signaling pathway together with Wnt5a. Biochemical and Biophysical Research Communications, 387, 207–211.PubMedGoogle Scholar
  273. 273.
    Saitoh, T., & Katoh, M. (2001). Molecular cloning and characterization of human WNT5B on chromosome 12p13.3 region. International Journal of Oncology, 19, 347–351.PubMedGoogle Scholar
  274. 274.
    Agalliu, D., Takada, S., Agalliu, I., McMahon, A. P., & Jessell, T. M. (2009). Motor neurons with axial muscle projections specified by Wnt4/5 signaling. Neuron, 61, 708–720.PubMedCentralPubMedGoogle Scholar
  275. 275.
    Cawthorn, W. P., Bree, A. J., Yao, Y., et al. (2012). Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a beta-catenin-dependent mechanism. Bone, 50, 477–489.PubMedCentralPubMedGoogle Scholar
  276. 276.
    Kirikoshi, H., Sekihara, H., & Katoh, M. (2001). WNT10A and WNT6, clustered in human chromosome 2q35 region with head-to-tail manner, are strongly coexpressed in SW480 cells. Biochemical and Biophysical Research Communications, 283, 798–805.PubMedGoogle Scholar
  277. 277.
    Wang, Q., Lu, J., Zhang, S., et al. (2013). Wnt6 is essential for stromal cell proliferation during decidualization in mice. Biology of Reproduction, 88, 5.PubMedGoogle Scholar
  278. 278.
    Carmon, K. S., & Loose, D. S. (2008). Wnt7a interaction with Fzd5 and detection of signaling activation using a split eGFP. Biochemical and Biophysical Research Communications, 368, 285–291.PubMedCentralPubMedGoogle Scholar
  279. 279.
    Yoshioka, S., King, M. L., Ran, S., et al. (2012). WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/beta-catenin pathway. Molecular Cancer Research: MCR, 10, 469–482.PubMedCentralPubMedGoogle Scholar
  280. 280.
    Carmon, K. S., & Loose, D. S. (2008). Secreted frizzled-related protein 4 regulates two Wnt7a signaling pathways and inhibits proliferation in endometrial cancer cells. Molecular Cancer Research: MCR, 6, 1017–1028.PubMedGoogle Scholar
  281. 281.
    Qu, Q., Sun, G., Murai, K., et al. (2013). Wnt7a regulates multiple steps of neurogenesis. Molecular and Cellular Biology, 33, 2551–2559.PubMedCentralPubMedGoogle Scholar
  282. 282.
    Ikegawa, S., Kumano, Y., Okui, K., Fujiwara, T., Takahashi, E., & Nakamura, Y. (1996). Isolation, characterization and chromosomal assignment of the human WNT7A gene. Cytogenetics and Cell Genetics, 74, 149–152.PubMedGoogle Scholar
  283. 283.
    Miller, C., & Sassoon, D. A. (1998). Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract. Development, 125, 3201–3211.PubMedGoogle Scholar
  284. 284.
    Parr, B. A., & McMahon, A. P. (1998). Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature, 395, 707–710.PubMedGoogle Scholar
  285. 285.
    Hall, A. C., Lucas, F. R., & Salinas, P. C. (2000). Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell, 100, 525–535.PubMedGoogle Scholar
  286. 286.
    Dunlap, K. A., Filant, J., Hayashi, K., et al. (2011). Postnatal deletion of Wnt7a inhibits uterine gland morphogenesis and compromises adult fertility in mice. Biology of Reproduction, 85, 386–396.PubMedCentralPubMedGoogle Scholar
  287. 287.
    Woods, C. G., Stricker, S., Seemann, P., et al. (2006). Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. American Journal of Human Genetics, 79, 402–408.PubMedCentralPubMedGoogle Scholar
  288. 288.
    Wang, Z., Shu, W., Lu, M. M., & Morrisey, E. E. (2005). Wnt7b activates canonical signaling in epithelial and vascular smooth muscle cells through interactions with Fzd1, Fzd10, and LRP5. Molecular and Cellular Biology, 25, 5022–5030.PubMedCentralPubMedGoogle Scholar
  289. 289.
    Brynczka, C., & Merrick, B. A. (2008). The p53 transcriptional target gene wnt7b contributes to NGF-inducible neurite outgrowth in neuronal PC12 cells. Differentiation; Research in Biological Diversity, 76, 795–808.PubMedCentralPubMedGoogle Scholar
  290. 290.
    Kirikoshi, H., Sekihara, H., & Katoh, M. (2001). Molecular cloning and characterization of human WNT7B. International Journal of Oncology, 19, 779–783.PubMedGoogle Scholar
  291. 291.
    Shu, W., Jiang, Y. Q., Lu, M. M., & Morrisey, E. E. (2002). Wnt7b regulates mesenchymal proliferation and vascular development in the lung. Development, 129, 4831–4842.PubMedGoogle Scholar
  292. 292.
    Parr, B. A., Cornish, V. A., Cybulsky, M. I., & McMahon, A. P. (2001). Wnt7b regulates placental development in mice. Developmental Biology, 237, 324–332.PubMedGoogle Scholar
  293. 293.
    Lako, M., Lindsay, S., Bullen, P., Wilson, D. I., Robson, S. C., & Strachan, T. (1998). A novel mammalian wnt gene, WNT8B, shows brain-restricted expression in early development, with sharply delimited expression boundaries in the developing forebrain. Human Molecular Genetics, 7, 813–822.PubMedGoogle Scholar
  294. 294.
    Fotaki, V., Larralde, O., Zeng, S., et al. (2010). Loss of Wnt8b has no overt effect on hippocampus development but leads to altered Wnt gene expression levels in dorsomedial telencephalon. Developmental Dynamics: An Official Publication of the American Association of Anatomists, 239, 284–296.Google Scholar
  295. 295.
    Spater, D., Hill, T. P., O’Sullivan, R. J., Gruber, M., Conner, D. A., & Hartmann, C. (2006). Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis. Development, 133, 3039–3049.PubMedGoogle Scholar
  296. 296.
    Park, J. S., Valerius, M. T., & McMahon, A. P. (2007). Wnt/beta-catenin signaling regulates nephron induction during mouse kidney development. Development, 134, 2533–2539.PubMedGoogle Scholar
  297. 297.
    Karner, C. M., Chirumamilla, R., Aoki, S., Igarashi, P., Wallingford, J. B., & Carroll, T. J. (2009). Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis. Nature Genetics, 41, 793–799.PubMedCentralPubMedGoogle Scholar
  298. 298.
    Carroll, T. J., Park, J. S., Hayashi, S., Majumdar, A., & McMahon, A. P. (2005). Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Developmental Cell, 9, 283–292.PubMedGoogle Scholar
  299. 299.
    Adaimy, L., Chouery, E., Megarbane, H., et al. (2007). Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia. American Journal of Human Genetics, 81, 821–828.PubMedCentralPubMedGoogle Scholar
  300. 300.
    Li, Y. H., Zhang, K., Ye, J. X., Lian, X. H., & Yang, T. (2011). Wnt10b promotes growth of hair follicles via a canonical Wnt signalling pathway. Clinical and Experimental Dermatology, 36, 534–540.PubMedGoogle Scholar
  301. 301.
    Hardiman, G., Kastelein, R. A., & Bazan, J. F. (1997). Isolation, characterization and chromosomal localization of human WNT10B. Cytogenetics and Cell Genetics, 77, 278–282.PubMedGoogle Scholar
  302. 302.
    Christodoulides, C., Scarda, A., Granzotto, M., et al. (2006). WNT10B mutations in human obesity. Diabetologia, 49, 678–684.PubMedGoogle Scholar
  303. 303.
    Van Camp, J. K., Zegers, D., Verhulst, S. L., et al. (2012). Mutation analysis of WNT10B in obese children, adolescents and adults. Endocrine.Google Scholar
  304. 304.
    Blattner, A., Huber, A. R., & Rothlisberger, B. (2010). Homozygous nonsense mutation in WNT10B and sporadic split-hand/foot malformation (SHFM) with autosomal recessive inheritance. American Journal of Medical Genetics Part A, 152A, 2053–2056.PubMedGoogle Scholar
  305. 305.
    Ugur, S. A., & Tolun, A. (2008). Homozygous WNT10b mutation and complex inheritance in Split-Hand/Foot Malformation. Human Molecular Genetics, 17, 2644–2653.PubMedGoogle Scholar
  306. 306.
    Ye, X., Wang, Y., Rattner, A., & Nathans, J. (2011). Genetic mosaic analysis reveals a major role for frizzled 4 and frizzled 8 in controlling ureteric growth in the developing kidney. Development, 138, 1161–1172.PubMedCentralPubMedGoogle Scholar
  307. 307.
    Vijayaragavan, K., Szabo, E., Bosse, M., Ramos-Mejia, V., Moon, R. T., & Bhatia, M. (2009). Noncanonical Wnt signaling orchestrates early developmental events toward hematopoietic cell fate from human embryonic stem cells. Cell Stem Cell, 4, 248–262.PubMedCentralPubMedGoogle Scholar
  308. 308.
    Friedman, M. S., Oyserman, S. M., & Hankenson, K. D. (2009). Wnt11 promotes osteoblast maturation and mineralization through R-spondin 2. Journal of Biological Chemistry, 284, 14117–14125.PubMedCentralPubMedGoogle Scholar
  309. 309.
    Ouko, L., Ziegler, T. R., Gu, L. H., Eisenberg, L. M., & Yang, V. W. (2004). Wnt11 signaling promotes proliferation, transformation, and migration of IEC6 intestinal epithelial cells. Journal of Biological Chemistry, 279, 26707–26715.PubMedCentralPubMedGoogle Scholar
  310. 310.
    Zhang, P., Cai, Y., Soofi, A., & Dressler, G. R. (2012). Activation of Wnt11 by transforming growth factor-beta drives mesenchymal gene expression through non-canonical Wnt protein signaling in renal epithelial cells. Journal of Biological Chemistry, 287, 21290–21302.PubMedCentralPubMedGoogle Scholar
  311. 311.
    Lako, M., Strachan, T., Bullen, P., Wilson, D. I., Robson, S. C., & Lindsay, S. (1998). Isolation, characterisation and embryonic expression of WNT11, a gene which maps to 11q13.5 and has possible roles in the development of skeleton, kidney and lung. Gene, 219, 101–110.PubMedGoogle Scholar
  312. 312.
    Majumdar, A., Vainio, S., Kispert, A., McMahon, J., & McMahon, A. P. (2003). Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development. Development, 130, 3175–3185.PubMedGoogle Scholar
  313. 313.
    Teh, M. T., Blaydon, D., Ghali, L. R., et al. (2007). Role for WNT16B in human epidermal keratinocyte proliferation and differentiation. Journal of Cell Science, 120, 330–339.PubMedGoogle Scholar
  314. 314.
    Fear, M. W., Kelsell, D. P., Spurr, N. K., & Barnes, M. R. (2000). Wnt-16a, a novel Wnt-16 isoform, which shows differential expression in adult human tissues. Biochemical and Biophysical Research Communications, 278, 814–820.PubMedGoogle Scholar
  315. 315.
    Medina-Gomez, C., Kemp, J. P., Estrada, K., et al. (2012). Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus. PLoS Genetics, 8, e1002718.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • J. K. Van Camp
    • 1
  • S. Beckers
    • 1
  • D. Zegers
    • 1
  • W. Van Hul
    • 1
  1. 1.Department of Medical GeneticsUniversity of AntwerpEdegemBelgium

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