Wnt Signaling pp 131-144 | Cite as

β-Catenin-Independent Wnt Pathways: Signals, Core Proteins, and Effectors

  • Richard G. James
  • William H. Conrad
  • Randall T. Moon
Part of the Methods in Molecular Biology™ book series (MIMB, volume 468)


Wnt signaling activates several distinct intracellular pathways, which are important for cell proliferation, differentiation, and polarity. Wnt proteins are secreted molecules that typically signal across the membrane via interaction with the transmembrane receptor Frizzled. Following interaction with Frizzled, the downstream effect of the most widely studied Wnt pathway is stabilization and nuclear translocation of the cytosolic protein, β-catenin. In this chapter, we discuss two β-catenin-independent branches of Wnt signaling: 1) Wnt/planar cell polarity (PCP), a Wnt pathway that signals through the small GTPases, Rho and Rac, to promote changes in the actin cytoskeleton, and 2) Wnt/Ca2+, a Wnt pathway that promotes intracellular calcium transients and negatively regulates the Wnt/β-catenin pathway. Finally, during the course of our discussion, we highlight areas that require future research.

Key words

Wnt Wnt/Ca Wnt/PCP 



This work was supported by the Howard Hughes Medical Institute and the National Institutes of Health (NIH) RO1 GM073887-03 to RTM.


  1. 1.
    Moon, R.T., A.D. Kohn, G.V. De Ferrari, and A. Kaykas. (2004) WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 5, 691–701.CrossRefPubMedGoogle Scholar
  2. 2.
    Seifert, J.R. and M. Mlodzik. (2007) Friz-zled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility. Nat Rev Genet. 8, 126–138.CrossRefPubMedGoogle Scholar
  3. 3.
    Wu, J., T.J. Klein, and M. Mlodzik. (2004) Subcellular localization of frizzled receptors, mediated by their cytoplasmic tails, regulates signaling pathway specificity. PLoS Biol. 2, E158.CrossRefPubMedGoogle Scholar
  4. 4.
    Amonlirdviman, K., N.A. Khare, D.R. Tree, W.S. Chen, J.D. Axelrod, and C.J. Tomlin. (2005) Mathematical modeling of planar cell polarity to understand domineering nonautonomy. Science. 307, 423–426.CrossRefPubMedGoogle Scholar
  5. 5.
    Yang, C.H., J.D. Axelrod, and M.A. Simon. (2002) Regulation of Frizzled by fat-like cadherins during planar polarity signaling in the Drosophila compound eye. Cell. 108, 675–688.CrossRefPubMedGoogle Scholar
  6. 6.
    Axelrod, J.D. (2001) Unipolar membrane association of Dishevelled mediates Frizzled planar cell polarity signaling. Genes Dev. 15, 1182–1187.PubMedGoogle Scholar
  7. 7.
    Das, G., A. Jenny, T.J. Klein, S. Eaton, and M. Mlodzik. (2004) Diego interacts with Prickle and Strabismus/Van Gogh to localize planar cell polarity complexes. Development. 131, 4467–4476.CrossRefPubMedGoogle Scholar
  8. 8.
    Strutt, D.I. (2001) Asymmetric localization of frizzled and the establishment of cell polarity in the Drosophila wing. Mol Cell. 7, 367–375.CrossRefPubMedGoogle Scholar
  9. 9.
    Bastock, R., H. Strutt, and D. Strutt. (2003) Strabismus is asymmetrically localised and binds to Prickle and Dishevelled during Drosophila planar polarity patterning. Development. 130, 3007–3014.CrossRefPubMedGoogle Scholar
  10. 10.
    Tree, D.R., J.M. Shulman, R. Rousset, M.P. Scott, D. Gubb, and J.D. Axelrod. (2002) Prickle mediates feedback amplification to generate asymmetric planar cell polarity signaling. Cell. 109, 371–381.CrossRefPubMedGoogle Scholar
  11. 11.
    Jenny, A., J. Reynolds-Kenneally, G. Das, M. Burnett, and M. Mlodzik. (2005) Diego and Prickle regulate Frizzled planar cell polarity signalling by competing for Dishevelled binding. Nat Cell Biol. 7, 691–697.CrossRefPubMedGoogle Scholar
  12. 12.
    Usui, T., Y. Shima, Y. Shimada, S. Hirano, R.W. Burgess, T.L. Schwarz, et al. (1999) Flamingo, a seven-pass transmembrane cad-herin, regulates planar cell polarity under the control of Frizzled. Cell. 98, 585–595.CrossRefPubMedGoogle Scholar
  13. 13.
    Adler, P.N., J. Charlton, K.H. Jones, and J. Liu. (1994) The cold-sensitive period for frizzled in the development of wing hair polarity ends prior to the start of hair morphogenesis. Mech Dev. 46, 101–107.CrossRefPubMedGoogle Scholar
  14. 14.
    Eaton, S., R. Wepf, and K. Simons. (1996) Roles for Rac1 and Cdc42 in planar polarization and hair outgrowth in the wing of Drosophila. J Cell Biol. 135, 1277–1289.CrossRefPubMedGoogle Scholar
  15. 15.
    Fanto, M., U. Weber, D.I. Strutt, and M. Mlodzik. (2000) Nuclear signaling by Rac and Rho GTPases is required in the establishment of epithelial planar polarity in the Drosophila eye. Curr Biol. 10, 979–988.CrossRefPubMedGoogle Scholar
  16. 16.
    Schwarz-Romond, T., C. Asbrand, J. Bakkers, M. Kuhl, H.J. Schaeffer, J. Huelsken, et al. (2002) The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev. 16, 2073–2084.CrossRefPubMedGoogle Scholar
  17. 17.
    Park, M. and R.T. Moon. (2002) The planar cell-polarity gene stbm regulates cell behaviour and cell fate in vertebrate embryos. Nat Cell Biol. 4, 20–25.CrossRefPubMedGoogle Scholar
  18. 18.
    Wallingford, J.B., B.A. Rowning, K.M. Vogeli, U. Rothbacher, S.E. Fraser, and R.M. Harland. (2000) Dishevelled controls cell polarity during Xenopus gastrulation. Nature. 405, 81–85.CrossRefPubMedGoogle Scholar
  19. 19.
    Wang, J., N.S. Hamblet, S. Mark, M.E. Dickinson, B.C. Brinkman, N. Segil, et al. (2006) Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation. Development. 133, 1767–1778.CrossRefPubMedGoogle Scholar
  20. 20.
    Formstone, C.J. and I. Mason. (2005) Combinatorial activity of Flamingo proteins directs convergence and extension within the early zebrafish embryo via the planar cell polarity pathway. Dev Biol. 282, 320–335.CrossRefPubMedGoogle Scholar
  21. 21.
    Takeuchi, M., J. Nakabayashi, T. Sakaguchi, T.S. Yamamoto, H. Takahashi, H. Takeda, et al. (2003) The prickle-related gene in vertebrates is essential for gastrulation cell movements. Curr Biol. 13, 674–679.CrossRefPubMedGoogle Scholar
  22. 22.
    Veeman, M.T., D.C. Slusarski, A. Kaykas, S.H. Louie, and R.T. Moon. (2003) Zebrafish prickle, a modulator of noncanonical Wnt/Fz signaling, regulates gastrulation movements. Curr Biol. 13, 680–685.CrossRefPubMedGoogle Scholar
  23. 23.
    Kilian, B., H. Mansukoski, F.C. Barbosa, F. Ulrich, M. Tada, and C.P. Heisenberg. (2003) The role of Ppt/Wnt5 in regulating cell shape and movement during zebrafish gastrulation. Mech Dev. 120, 467–476.CrossRefPubMedGoogle Scholar
  24. 24.
    Heisenberg, C.P., M. Tada, G.J. Rauch, L. Saude, M.L. Concha, R. Geisler, et al. (2000) Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature. 405, 76–81.CrossRefPubMedGoogle Scholar
  25. 25.
    Carreira-Barbosa, F., M.L. Concha, M. Takeuchi, N. Ueno, S.W. Wilson, and M. Tada. (2003) Prickle 1 regulates cell movements during gastrulation and neuronal migration in zebrafish. Development. 130, 4037–4046.CrossRefPubMedGoogle Scholar
  26. 26.
    Moeller, H., A. Jenny, H.J. Schaeffer, T. Schwarz-Romond, M. Mlodzik, M. Ham-merschmidt, et al. (2006) Diversin regulates heart formation and gastrulation movements in development. Proc Natl Acad Sci U S A. 103, 15900–15905.CrossRefPubMedGoogle Scholar
  27. 27.
    Axelrod, J.D., J.R. Miller, J.M. Shulman, R.T. Moon, and N. Perrimon. (1998) Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev. 12, 2610–2622.CrossRefPubMedGoogle Scholar
  28. 28.
    Boutros, M., J. Mihaly, T. Bouwmeester, and M. Mlodzik. (2000) Signaling specificity by Frizzled receptors in Drosophila. Science. 288, 1825–1828.CrossRefPubMedGoogle Scholar
  29. 29.
    Yanagawa, S., F. van Leeuwen, A. Wodarz, J. Klingensmith, and R. Nusse. (1995) The dishevelled protein is modified by wingless signaling in Drosophila. Genes Dev. 9, 1087–1097.CrossRefPubMedGoogle Scholar
  30. 30.
    Gonzalez-Sancho, J.M., K.R. Brennan, L.A. Castelo-Soccio, and A.M. Brown. (2004) Wnt proteins induce dishevelled phosphor-ylation via an LRP5/6- independent mechanism, irrespective of their ability to stabilize beta-catenin. Mol Cell Biol. 24, 4757–4768.CrossRefPubMedGoogle Scholar
  31. 31.
    Liu, T., A.J. DeCostanzo, X. Liu, H. Wang, S. Hallagan, R.T. Moon, et al. (2001) G protein signaling from activated rat frizzled-1 to the beta-catenin-Lef-Tcf pathway. Science. 292, 1718–1722.CrossRefPubMedGoogle Scholar
  32. 32.
    Cong, F., L. Schweizer, and H. Varmus. (2004) Casein kinase Iepsilon modulates the signaling specificities of dishevelled. Mol Cell Biol. 24, 2000–2011.CrossRefPubMedGoogle Scholar
  33. 33.
    Peters, J.M., R.M. McKay, J.P. McKay, and J.M. Graff. (1999) Casein kinase I transduces Wnt signals. Nature. 401, 345–350.CrossRefPubMedGoogle Scholar
  34. 34.
    Swiatek, W., I.C. Tsai, L. Klimowski, A. Pepler, J. Barnette, H.J. Yost, et al. (2004) Regulation of casein kinase I epsilon activity by Wnt signaling. J Biol Chem. 279, 13011–13017.CrossRefPubMedGoogle Scholar
  35. 35.
    Klein, T.J., A. Jenny, A. Djiane, and M. Mlodzik. (2006) CKIepsilon/discs overgrown promotes both Wnt-Fz/beta-catenin and Fz/PCP signaling in Drosophila. Curr Biol. 16, 1337–1343.CrossRefPubMedGoogle Scholar
  36. 36.
    Strutt, H., M.A. Price, and D. Strutt. (2006) Planar polarity is positively regulated by casein kinase Iepsilon in Drosophila. Curr Biol. 16, 1329–1336.CrossRefPubMedGoogle Scholar
  37. 37.
    Tao, Q., C. Yokota, H. Puck, M. Kofron, B. Birsoy, D. Yan, et al. (2005) Maternal wnt11 activates the canonical wnt signaling pathway required for axis formation in Xenopus embryos. Cell. 120, 857–871.CrossRefPubMedGoogle Scholar
  38. 38.
    Lu, W., V. Yamamoto, B. Ortega, and D. Baltimore. (2004) Mammalian Ryk is a Wnt coreceptor required for stimulation of neu-rite outgrowth. Cell. 119, 97–108.CrossRefPubMedGoogle Scholar
  39. 39.
    Hikasa, H., M. Shibata, I. Hiratani, and M. Taira. (2002) The Xenopus receptor tyrosine kinase Xror2 modulates morpho-genetic movements of the axial mesoderm and neuroectoderm via Wnt signaling. Development. 129, 5227–5239.PubMedGoogle Scholar
  40. 40.
    Mikels, A.J. and R. Nusse. (2006) Purified Wnt5a protein activates or inhibits beta-cat-enin-TCF signaling depending on receptor context. PLoS Biol. 4, e115.CrossRefPubMedGoogle Scholar
  41. 41.
    Schambony, A. and D. Wedlich. (2007) Wnt-5A/Ror2 regulate expression of XPAPC through an alternative noncanonical signaling pathway. Dev Cell. 12, 779–792.CrossRefPubMedGoogle Scholar
  42. 42.
    Keeble, T.R., M.M. Halford, C. Seaman, N. Kee, M. Macheda, R.B. Anderson, et al. (2006) The Wnt receptor Ryk is required for Wnt5a-mediated axon guidance on the contralateral side of the corpus callosum. J Neurosci. 26, 5840–5848.CrossRefPubMedGoogle Scholar
  43. 43.
    Yoshikawa, S., R.D. McKinnon, M. Kokel, and J.B. Thomas. (2003) Wnt-mediated axon guidance via the Drosophila Derailed receptor. Nature. 422, 583–588.CrossRefPubMedGoogle Scholar
  44. 44.
    Lu, X., A.G. Borchers, C. Jolicoeur, H. Ray-burn, J.C. Baker, and M. Tessier-Lavigne. (2004) PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature. 430, 93–98.CrossRefPubMedGoogle Scholar
  45. 45.
    He, X., J.P. Saint-Jeannet, Y. Wang, J. Nathans, I. Dawid, and H. Varmus. (1997) A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science. 275, 1652–1654.CrossRefPubMedGoogle Scholar
  46. 46.
    Habas, R., Y. Kato, and X. He. (2001) Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1. Cell. 107, 843–854.CrossRefPubMedGoogle Scholar
  47. 47.
    Price, M.H., D.M. Roberts, B.M. McCartney, E. Jezuit, and M. Peifer. (2006) Cytoskeletal dynamics and cell signaling during planar polarity establishment in the Drosophila embryonic denticle. J Cell Sci. 119, 403–415.CrossRefPubMedGoogle Scholar
  48. 48.
    Harris, K.E. and S.K. Beckendorf. (2007) Different Wnt signals act through the Frizzled and RYK receptors during Drosophila salivary gland migration. Development. 134, 2017–2025.CrossRefPubMedGoogle Scholar
  49. 49.
    Wong, L.L. and P.N. Adler. (1993) Tissue polarity genes of Drosophila regulate the subcellular location for prehair initiation in pupal wing cells. J Cell Biol. 123, 209–221.CrossRefPubMedGoogle Scholar
  50. 50.
    Gubb, D. and A. Garcia-Bellido. (1982) A genetic analysis of the determination of cuticular polarity during development in Drosophila melanogaster. J Embryol Exp Morphol. 68, 37–57.PubMedGoogle Scholar
  51. 51.
    Hall, A. (1998) Rho GTPases and the actin cytoskeleton. Science. 279, 509–514.CrossRefPubMedGoogle Scholar
  52. 52.
    Ridley, A.J. and A. Hall. (1992) The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 70, 389–399.CrossRefPubMedGoogle Scholar
  53. 53.
    Ridley, A.J., H.F. Paterson, C.L. Johnston, D. Diekmann, and A. Hall. (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell. 70, 401–410.CrossRefPubMedGoogle Scholar
  54. 54.
    Boutros, M., N. Paricio, D.I. Strutt, and M. Mlodzik. (1998) Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling. Cell. 94, 109–118.CrossRefPubMedGoogle Scholar
  55. 55.
    Zhu, S., L. Liu, V. Korzh, Z. Gong, and B.C. Low. (2006) RhoA acts downstream of Wnt5 and Wnt11 to regulate convergence and extension movements by involving effectors Rho kinase and Diaphanous: use of zebrafish as an in vivo model for GTPase signaling. Cell Signal. 18, 359–372.CrossRefPubMedGoogle Scholar
  56. 56.
    Tahinci, E. and K. Symes. (2003) Distinct functions of Rho and Rac are required for convergent extension during Xenopus gas-trulation. Dev Biol. 259, 318–335.CrossRefPubMedGoogle Scholar
  57. 57.
    Marlow, F., J. Topczewski, D. Sepich, and L. Solnica-Krezel. (2002) Zebrafish Rho kinase 2 acts downstream of Wnt11 to mediate cell polarity and effective convergence and extension movements. Curr Biol. 12, 876–884.CrossRefPubMedGoogle Scholar
  58. 58.
    Winter, C.G., B. Wang, A. Ballew, A. Royou, R. Karess, J.D. Axelrod, et al. (2001) Dro-sophila Rho-associated kinase (Drok) links Frizzled-mediated planar cell polarity signaling to the actin cytoskeleton. Cell. 105, 81–91.CrossRefPubMedGoogle Scholar
  59. 59.
    Kim, G.H. and J.K. Han. (2005) JNK and ROKalpha function in the noncanonical Wnt/RhoA signaling pathway to regulate Xenopus convergent extension movements. Dev Dyn. 232, 958–968.CrossRefPubMedGoogle Scholar
  60. 60.
    Strutt, D.I., U. Weber, and M. Mlodzik. (1997) The role of RhoA in tissue polarity and Frizzled signalling. Nature. 387, 292–295.CrossRefPubMedGoogle Scholar
  61. 61.
    Yamanaka, H., T. Moriguchi, N. Masuyama, M. Kusakabe, H. Hanafusa, R. Takada, et al. (2002) JNK functions in the non-canonical Wnt pathway to regulate convergent extension movements in vertebrates. EMBO Rep. 3, 69–75.CrossRefPubMedGoogle Scholar
  62. 62.
    Kohn, A.D. and R.T. Moon. (2005) Wnt and calcium signaling: beta-catenin-inde-pendent pathways. Cell Calcium. 38, 439–446.CrossRefPubMedGoogle Scholar
  63. 63.
    Slusarski, D.C. and F. Pelegri. (2007) Calcium signaling in vertebrate embryonic patterning and morphogenesis. Dev Biol. 307, 1–13.CrossRefPubMedGoogle Scholar
  64. 64.
    Webb, S.E. and A.L. Miller. (2003) Calcium signalling during embryonic development. Nat Rev Mol Cell Biol. 4, 539–551.CrossRefPubMedGoogle Scholar
  65. 65.
    Dejmek, J., A. Safholm, C. Kamp Nielsen, T. Andersson, and K. Leandersson. (2006) Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1alpha signaling in human mammary epithelial cells. Mol Cell Biol. 26, 6024– 6036.CrossRefPubMedGoogle Scholar
  66. 66.
    Ma, L. and H.Y. Wang. (2006) Suppression of cyclic GMP-dependent protein kinase is essential to the Wnt/cGMP/Ca2+ pathway. J Biol Chem. 281, 30990–31001.CrossRefPubMedGoogle Scholar
  67. 67.
    Reinhard, E., H. Yokoe, K.R. Niebling, N.L. Allbritton, M.A. Kuhn, and T. Meyer. (1995) Localized calcium signals in early zebrafish development. Dev Biol. 170, 50–61.CrossRefPubMedGoogle Scholar
  68. 68.
    Slusarski, D.C., V.G. Corces, and R.T. Moon. (1997) Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phos-phatidylinositol signalling. Nature. 390, 410–413.CrossRefPubMedGoogle Scholar
  69. 69.
    Slusarski, D.C., J. Yang-Snyder, W.B. Busa, and R.T. Moon. (1997) Modulation of embryonic intracellular Ca2+ signaling by Wnt-5A. Dev Biol. 182, 114–120.CrossRefPubMedGoogle Scholar
  70. 70.
    Gilland, E., A.L. Miller, E. Karplus, R. Baker, and S.E. Webb. (1999) Imaging of multicellular large-scale rhythmic calcium waves during zebrafish gastrulation. Proc Natl Acad Sci U S A. 96, 157–161.CrossRefPubMedGoogle Scholar
  71. 71.
    Wallingford, J.B., A.J. Ewald, R.M. Harland, and S.E. Fraser. (2001) Calcium signaling during convergent extension in Xenopus. Curr Biol. 11, 652–661.CrossRefPubMedGoogle Scholar
  72. 72.
    Westfall, T.A., R. Brimeyer, J. Twedt, J. Gladon, A. Olberding, M. Furutani-Seiki, et al. (2003) Wnt-5/pipetail functions in vertebrate axis formation as a negative regulator of Wnt/beta-catenin activity. J Cell Biol. 162, 889–898.CrossRefPubMedGoogle Scholar
  73. 73.
    Kuhl, M., L.C. Sheldahl, C.C. Malbon, and R.T. Moon. (2000) Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus. J Biol Chem. 275, 12701–12711.CrossRefPubMedGoogle Scholar
  74. 74.
    Sheldahl, L.C., D.C. Slusarski, P. Pandur, J.R. Miller, M. Kuhl, and R.T. Moon. (2003) Dishevelled activates Ca2+ flux, PKC, and CamKII in vertebrate embryos. J Cell Biol. 161, 769–777.CrossRefPubMedGoogle Scholar
  75. 75.
    Sheldahl, L.C., M. Park, C.C. Malbon, and R.T. Moon. (1999) Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Curr Biol. 9, 695–698.CrossRefPubMedGoogle Scholar
  76. 76.
    Saneyoshi, T., S. Kume, Y. Amasaki, and K. Mikoshiba. (2002) The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos. Nature. 417, 295–299.CrossRefPubMedGoogle Scholar
  77. 77.
    Westfall, T.A., B. Hjertos, and D.C. Slusarski. (2003) Requirement for intracellular calcium modulation in zebrafish dorsal-ventral patterning. Dev Biol. 259, 380–391.CrossRefPubMedGoogle Scholar
  78. 78.
    Gwak, J., M. Cho, S.J. Gong, J. Won, D.E. Kim, E.Y. Kim, et al. (2006) Protein-kinase-C-mediated beta-catenin phosphorylation negatively regulates the Wnt/beta-catenin pathway. J Cell Sci. 119, 4702–4709.CrossRefPubMedGoogle Scholar
  79. 79.
    Ishitani, T., S. Kishida, J. Hyodo-Miura, N. Ueno, J. Yasuda, M. Waterman, 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. Mol Cell Biol. 23, 131–139.CrossRefPubMedGoogle Scholar
  80. 80.
    Ishitani, T., J. Ninomiya-Tsuji, and K. Matsumoto. (2003) Regulation of lym-phoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphoryla-tion in Wnt/beta-catenin signaling. Mol Cell Biol. 23, 1379–1389.CrossRefPubMedGoogle Scholar
  81. 81.
    Ishitani, T., J. Ninomiya-Tsuji, S. Nagai, M. Nishita, M. Meneghini, N. Barker, et al. (1999) The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature. 399, 798–802.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Richard G. James
    • 1
  • William H. Conrad
    • 1
  • Randall T. Moon
    • 1
  1. 1.Howard Hughes Medical Institute, Department of Pharmacology, and Institute for Stem Cell and Regenerative MedicineUniversity of Washington School of MedicineSeattleUSA

Personalised recommendations