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Non-canonical Wnt signaling pathways in hematopoiesis

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Abstract

Hematopoietic stem cells (HSCs) are a rare population of cells that are responsible for life-long generation of blood cells of all lineages. In order to maintain their numbers, HSCs must establish a balance between the opposing cell fates of self-renewal and initiation of hematopoietic differentiation. Multiple signaling pathways have been implicated in the regulation of HSC cell fate. One such set of pathways are those activated by the Wnt family of ligands. The function of the canonical Wnt signaling pathway, which utilizes β-catenin to regulate gene expression, has been extensively studied in hematopoiesis. However, there is a growing body of evidence that the other Wnt signaling pathways, termed non-canonical, also play an important role. In this review, we will discuss the regulation of hematopoiesis by the Wnt signaling pathways, focusing on the potential functions of non-canonical Wnt signaling pathways.

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References

  1. Lemischka IR, Raulet DH, Mulligan RC. Developmental potential and dynamic behavior of hematopoietic stem cells. Cell. 1986;45:917–27.

    Article  PubMed  CAS  Google Scholar 

  2. Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science. 1988;241:58–62.

    Article  PubMed  CAS  Google Scholar 

  3. Smith LG, Weissman IL, Heimfeld S. Clonal analysis of hematopoietic stem-cell differentiation in vivo. Proc Natl Acad Sci USA. 1991;88:2788–92.

    Article  PubMed  CAS  Google Scholar 

  4. Harrison DE, Astle CM, Lerner C. Number and continuos proliferation pattern of transplanted primitive immunohematopoietic stem cells. Proc Natl Acad Sci. 1988;85:822–6.

    Article  PubMed  CAS  Google Scholar 

  5. Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood. 1993;81:2844–53.

    PubMed  CAS  Google Scholar 

  6. Suda J, Suda T, Ogawa M. Analysis of differentiation of mouse hemopoietic stem cells in culture by sequential replating of paired progenitors. Blood. 1984;64:393–9.

    PubMed  CAS  Google Scholar 

  7. Leary AG, Ogawa M, Strauss LC, Civin CI. Single cell origin of multilineage colonies in culture. evidence that differentiation of multipotent progenitors and restriction of proliferative potential of monopotent progenitors are stochastic processes. J Clin Invest. 1984;74:2193–7.

    Article  PubMed  CAS  Google Scholar 

  8. Wu M, Kwon HY, Rattis F, Blum J, Zhao C, Ashkenazi R, et al. Imaging hematopoietic precursor division in real time. Cell Stem Cell. 2007;1:541–54.

    Article  PubMed  CAS  Google Scholar 

  9. Bowie MB, McKnight KD, Kent DG, McCaffrey L, Hoodless PA, Eaves CJ. Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. J Clin Invest. 2006;116:2808–16.

    Article  PubMed  CAS  Google Scholar 

  10. Passegue E, Wagers AJ, Giuriato S, Anderson WC, Weissman IL. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med. 2005;202:1599–611.

    Article  PubMed  CAS  Google Scholar 

  11. Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008;135:1118–29.

    Article  PubMed  CAS  Google Scholar 

  12. Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118:149–61.

    Article  PubMed  CAS  Google Scholar 

  13. Hermitte F, de la Grange PB, Belloc F, Praloran V, Ivanovic Z. Very low O2 concentration (0.1%) favors G0 return of dividing CD34 + cells. Stem Cells. 2006;24:65–73.

    Article  PubMed  Google Scholar 

  14. Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science. 2000;287:1804–8.

    Article  PubMed  CAS  Google Scholar 

  15. Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y, et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2007;1:685–97.

    Article  PubMed  CAS  Google Scholar 

  16. Liu Y, Elf SE, Miyata Y, Sashida G, Huang G, Di Giandomenico S, et al. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell. 2009;4:37–48.

    Article  PubMed  CAS  Google Scholar 

  17. Viatour P, Somervaille TC, Venkatasubrahmanyam S, Kogan S, McLaughlin ME, Weissman IL, et al. Hematopoietic stem cell quiescence is maintained by compound contributions of the retinoblastoma gene family. Cell Stem Cell. 2008;3:416–28.

    Article  PubMed  CAS  Google Scholar 

  18. Kondo M, Weissman IL, Akashi K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell. 1997;91:661–72.

    Article  PubMed  CAS  Google Scholar 

  19. Akashi K, Traver D, Miyamoto T, Weissman I. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature. 2000;404:193–7.

    Article  PubMed  CAS  Google Scholar 

  20. Adolfsson J, Mansson R, Buza-Vidas N, Hultquist A, Liuba K, Jensen CT, et al. Identification of Flt3 + lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell. 2005;121:295–306.

    Article  PubMed  CAS  Google Scholar 

  21. Ikuta K, Weissman IL. Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proc Natl Acad Sci USA. 1992;89:1502–6.

    Article  PubMed  CAS  Google Scholar 

  22. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science. 1996;273:242–5.

    Article  PubMed  CAS  Google Scholar 

  23. Christensen JL, Weissman IL. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci USA. 2001;98:14541–6.

    Article  PubMed  CAS  Google Scholar 

  24. Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121:1109–21.

    Article  PubMed  CAS  Google Scholar 

  25. Gothot A, van der Loo JC, Clapp DW, Srour EF. Cell cycle-related changes in repopulating capacity of human mobilized peripheral blood CD34(+) cells in non-obese diabetic/severe combined immune-deficient mice. Blood. 1998;92:2641–9.

    PubMed  CAS  Google Scholar 

  26. Fleming WH, Alpern EJ, Uchida N, Ikuta K, Spangrude GJ, Weissman IL. Functional heterogeneity is associated with the cell cycle status of murine hematopoietic stem cells. J Cell Biol. 1993;122:897–902.

    Article  PubMed  CAS  Google Scholar 

  27. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.

    Article  PubMed  CAS  Google Scholar 

  28. Semenov MV, Habas R, Macdonald BT, He X. SnapShot: noncanonical Wnt signaling pathways. Cell. 2007;131:1378.

    Article  PubMed  Google Scholar 

  29. Mosimann C, Hausmann G, Basler K. Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol. 2009;10:276–86.

    Article  PubMed  CAS  Google Scholar 

  30. Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y, Macke JP, et al. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature. 1996;382:225–30.

    Article  PubMed  CAS  Google Scholar 

  31. Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC. An LDL-receptor-related protein mediates Wnt signalling in mice. Nature. 2000;407:535–8.

    Article  PubMed  CAS  Google Scholar 

  32. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, et al. LDL-receptor-related proteins in Wnt signal transduction. Nature. 2000;407:530–5.

    Article  PubMed  CAS  Google Scholar 

  33. Liu C, Kato Y, Zhang Z, Do VM, Yankner BA, He X. beta-Trcp couples beta-catenin phosphorylation-degradation and regulates xenopus axis formation. Proc Natl Acad Sci USA. 1999;96:6273–8.

    Article  PubMed  CAS  Google Scholar 

  34. Schwarz-Romond T, Fiedler M, Shibata N, Butler PJ, Kikuchi A, Higuchi Y, et al. The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization. Nat Struct Mol Biol. 2007;14:484–92.

    Article  PubMed  CAS  Google Scholar 

  35. Zeng X, Huang H, Tamai K, Zhang X, Harada Y, Yokota C, et al. Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development. 2008;135:367–75.

    Article  PubMed  CAS  Google Scholar 

  36. Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, et al. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature. 1996;382:638–42.

    Article  PubMed  CAS  Google Scholar 

  37. van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, et al. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell. 1997;88:789–99.

    Article  PubMed  Google Scholar 

  38. Slusarski DC, Corces VG, Moon RT. Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature. 1997;390:410–3.

    Article  PubMed  CAS  Google Scholar 

  39. Ahumada A, Slusarski DC, Liu X, Moon RT, Malbon CC, Wang HY. Signaling of rat Frizzled-2 through phosphodiesterase and cyclic GMP. Science. 2002;298:2006–10.

    Article  PubMed  CAS  Google Scholar 

  40. Ma L, Wang HY. Mitogen-activated protein kinase p38 regulates the Wnt/cyclic GMP/Ca2 + non-canonical pathway. J Biol Chem. 2007;282:28980–90.

    Article  PubMed  CAS  Google Scholar 

  41. Sheldahl LC, Park M, Malbon CC, Moon RT. Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Curr Biol. 1999;9:695–8.

    Article  PubMed  CAS  Google Scholar 

  42. Kuhl M, Sheldahl LC, Malbon CC, Moon RT. Ca(2 +)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in xenopus. J Biol Chem. 2000;275:12701–11.

    Article  PubMed  CAS  Google Scholar 

  43. Saneyoshi T, Kume S, Amasaki Y, Mikoshiba K. The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in xenopus embryos. Nature. 2002;417:295–9.

    Article  PubMed  CAS  Google Scholar 

  44. Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, et al. 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. 2003;23:131–9.

    Article  PubMed  CAS  Google Scholar 

  45. Torres MA, Yang-Snyder JA, Purcell SM, DeMarais AA, McGrew LL, Moon RT. 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. J Cell Biol. 1996;133:1123–37.

    Article  PubMed  CAS  Google Scholar 

  46. Topol L, Jiang X, Choi H, Garrett-Beal L, Carolan PJ, Yang Y. Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent beta-catenin degradation. J Cell Biol. 2003;162:899–908.

    Article  PubMed  CAS  Google Scholar 

  47. Mikels AJ, Nusse R. Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol. 2006;4:e115.

    Article  PubMed  CAS  Google Scholar 

  48. Bryja V, Andersson ER, Schambony A, Esner M, Bryjova L, Biris KK, et al. The extracellular domain of Lrp5/6 inhibits noncanonical Wnt signaling in vivo. Mol Biol Cell. 2009;20:924–36.

    Article  PubMed  CAS  Google Scholar 

  49. Nemeth MJ, Bodine DM. Regulation of hematopoiesis and the hematopoietic stem cell niche by Wnt signaling pathways. Cell Res. 2007;17:746–58.

    Article  PubMed  CAS  Google Scholar 

  50. Malhotra S, Kincade PW. Wnt-related molecules and signaling pathway equilibrium in hematopoiesis. Cell Stem Cell. 2009;4:27–36.

    Article  PubMed  CAS  Google Scholar 

  51. Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol. 2006;7:1048–56.

    Article  PubMed  CAS  Google Scholar 

  52. Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG, et al. Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol. 2006;7:1037–47.

    Article  PubMed  CAS  Google Scholar 

  53. Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12:528–41.

    Article  PubMed  CAS  Google Scholar 

  54. Cobas M, Wilson A, Ernst B, Mancini SJ, MacDonald HR, Kemler R, et al. Beta-catenin is dispensable for hematopoiesis and lymphopoiesis. J Exp Med. 2004;199:221–9.

    Article  PubMed  CAS  Google Scholar 

  55. Luis TC, Weerkamp F, Naber BA, Baert MR, de Haas EF, Nikolic T, et al. Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation. Blood. 2009;113:546–54.

    Article  PubMed  CAS  Google Scholar 

  56. Murdoch B, Chadwick K, Martin M, Shojaei F, Shah KV, Gallacher L, et al. Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo. Proc Natl Acad Sci USA. 2003;100:3422–7.

    Article  PubMed  CAS  Google Scholar 

  57. Nemeth MJ, Topol L, Anderson SM, Yang Y, Bodine DM. Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation. Proc Natl Acad Sci USA. 2007;104:15436–41.

    Article  PubMed  Google Scholar 

  58. Louis I, Heinonen KM, Chagraoui J, Vainio S, Sauvageau G, Perreault C. The signaling protein Wnt4 enhances thymopoiesis and expands multipotent hematopoietic progenitors through beta-catenin-independent signaling. Immunity. 2008;29:57–67.

    Article  PubMed  CAS  Google Scholar 

  59. Mitsutake N, Namba H, Shklyaev SS, Tsukazaki T, Ohtsuru A, Ohba M, et al. PKC delta mediates ionizing radiation-induced activation of c-Jun NH(2)-terminal kinase through MKK7 in human thyroid cells. Oncogene. 2001;20:989–96.

    Article  PubMed  CAS  Google Scholar 

  60. Vijayaragavan K, Szabo E, Bosse M, Ramos-Mejia V, Moon RT, Bhatia M. Noncanonical Wnt signaling orchestrates early developmental events toward hematopoietic cell fate from human embryonic stem cells. Cell Stem Cell. 2009;4:248–62.

    Article  PubMed  CAS  Google Scholar 

  61. Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta. 2003;1653:1–24.

    PubMed  CAS  Google Scholar 

  62. Liang H, Chen Q, Coles AH, Anderson SJ, Pihan G, Bradley A, et al. Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell. 2003;4:349–60.

    Article  PubMed  CAS  Google Scholar 

  63. Roman-Gomez J, Jimenez-Velasco A, Cordeu L, Vilas-Zornoza A, San Jose-Eneriz E, Garate L, et al. WNT5A, a putative tumour suppressor of lymphoid malignancies, is inactivated by aberrant methylation in acute lymphoblastic leukaemia. Eur J Cancer. 2007;43:2736–46.

    Article  PubMed  CAS  Google Scholar 

  64. Martin V, Agirre X, Jimenez-Velasco A, Jose-Eneriz ES, Cordeu L, Garate L, et al. Methylation status of Wnt signaling pathway genes affects the clinical outcome of Philadelphia-positive acute lymphoblastic leukemia. Cancer Sci. 2008;99:1865–8.

    Article  PubMed  CAS  Google Scholar 

  65. Ysebaert L, Chicanne G, Demur C, De Toni F, Prade-Houdellier N, Ruidavets JB, et al. Expression of beta-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. Leukemia. 2006;20:1211–6.

    Article  PubMed  CAS  Google Scholar 

  66. Safholm A, Tuomela J, Rosenkvist J, Dejmek J, Harkonen P, Andersson T. The Wnt-5a-derived hexapeptide Foxy-5 inhibits breast cancer metastasis in vivo by targeting cell motility. Clin Cancer Res. 2008;14:6556–63.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, 14263, NY, USA

    Kathleen Kokolus & Michael J. Nemeth

  2. Department of Medicine, Roswell Park Cancer Institute, 5303 Buffalo Life Sciences Center, Buffalo, 14263, NY, USA

    Michael J. Nemeth

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  1. Kathleen Kokolus
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Correspondence to Michael J. Nemeth.

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Kokolus, K., Nemeth, M.J. Non-canonical Wnt signaling pathways in hematopoiesis. Immunol Res 46, 155–164 (2010). https://doi.org/10.1007/s12026-009-8116-7

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