Wnt Signaling in Stem Cells



Wnt signaling pathways play divergent roles during development, normal homeostasis and disease. Wnt signaling is also critically important in stem cell biology. It has been demonstrated to be involved in both the proliferation and differentiation of stem and progenitor populations. Wnt/β-catenin signaling also plays a critical role in lineage decision/commitment. These dramatically different outcomes upon activation of the Wnt signaling cascade has fueled enormous controversy concerning the role of Wnt signaling in maintenance of potency and induction of differentiation. Tight regulation and controlled coordination of the Wnt signaling cascade is required to maintain the balance between proliferation and differentiation. The diverse and titrated responses that result from the activation of the Wnt signaling pathway however begs the question of how the Wnt signaling network integrates the various inputs that a cell receives to elicit the correct and coordinated responses.

Until recently, a rationale for the dichotomous behavior of Wnt/beta-catenin signaling in controlling both proliferation and differentiation has been unclear. Using a selective antagonist of the CBP/beta-catenin interaction that we identified using a chemical genomic approach, we have developed a model to explain the divergent activities of Wnt/beta-catenin signaling. Our model highlights the distinct and non-redundant roles of the coactivators CBP and p300 in the Wnt/beta-catenin signaling cascade. The critical feature of the model is that CBP/catenin mediated transcription is critical for proliferation and stem cell/progenitor cell maintenance; whereas p300/catenin mediated transcription leads to the differentiation program. The ‘decision’ to partner with either CBP or p300 is the first key decision point to initiate either a proliferative or a differentiative program, respectively. This initiation of proliferation or differentiation is followed by additional epigenetic modifications as well as the recruitment of additional transcription factors for both subsequent expansion of transient amplifying populations and/or lineage commitment.

The ultimate decision for a cell to either initiate differentiation, or not, must be integrated and funneled down into a decision point. We propose that essentially all cellular information – i.e. from other signaling pathways, nutrient levels, etc. – is funneled down into a choice of coactivators usage, either CBP or p300, by their interacting partner beta-catenin (or catenin-like molecules in the absence of beta-catenin) to make the critical decision to either remain quiescent, or once entering cycle to proliferate without differentiation or to initiate the differentiation process.


Role of coactivators CBP and p300 Wnt signaling Stem cells Potency 


  1. Blum B, Bar-Nur O, Golan-Lev T, Benvenisty N (2009) The anti-apoptotic gene survivin contributes to teratoma formation by human embryonic stem cells. Nat Biotechnol 27:281–287CrossRefPubMedGoogle Scholar
  2. Chenn A, Walsh CA (2002) Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297:365–369CrossRefPubMedGoogle Scholar
  3. Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, Moon RT, Teo JL, Kim HY, Moon SH, Ha JR, Kahn M (2004) A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci U S A 101:12682–12687CrossRefPubMedGoogle Scholar
  4. Fukuda S, Foster RG, Porter SB, Pelus LM (2002) The antiapoptosis protein survivin is associated with cell cycle entry of normal cord blood CD34(+) cells and modulates cell cycle and proliferation of mouse hematopoietic progenitor cells. Blood 100:2463–2471CrossRefPubMedGoogle Scholar
  5. Hamburger AW, Salmon SE (1980) Development of a bioassay for human myeloma colony-forming cells. Prog Clin Biol Res 48:23–41.Google Scholar
  6. Hasegawa K, Teo J.-T, Suemori H, Nakatsuji N, Pera M, Kahn M (2009) Development of a novel xeno-free human embryonic stem cell culture system using small molecules. In ISSCR 7th Annual Meeting, July 8–11, 2009, Barcelona, SpainGoogle Scholar
  7. Hay DC, Sutherland L, Clark J, Burdon T (2004) Oct-4 knockdown induces similar patterns of endoderm and trophoblast differentiation markers in human and mouse embryonic stem cells. Stem Cells 22:225–235CrossRefPubMedGoogle Scholar
  8. Hirschmann-Jax C, Foster AE, Wulf GG, Goodell MA, Brenner MK (2005) A distinct “side population” of cells in human tumor cells: implications for tumor biology and therapy. Cell Cycle 4:203–205CrossRefPubMedGoogle Scholar
  9. Jeannet G, Scheller M, Scarpellino L, Duboux S, Gardiol N, Back J, Kuttler F, Malanchi I, Birchmeier W, Leutz A, Huelsken J, Held W (2008) Long-term, multilineage hematopoiesis occurs in the combined absence of beta-catenin and gamma-catenin. Blood 111:142–149CrossRefPubMedGoogle Scholar
  10. Komiya Y, Habas R (2008) Wnt signal transduction pathways. Organogenesis 4:68–75CrossRefPubMedGoogle Scholar
  11. Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG, Golub TR, Armstrong SA (2006) Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442:818–822CrossRefPubMedGoogle Scholar
  12. Le NH, Franken P, Fodde R (2008) Tumour-stroma interactions in colorectal cancer: converging on beta-catenin activation and cancer stemness. Br J Cancer 98:1886–1893CrossRefPubMedGoogle Scholar
  13. Ma H, Nguyen C, Lee KS, Kahn M (2005) Differential roles for the coactivators CBP and p300 on TCF/beta-catenin-mediated survivin gene expression. Oncogene 24:3619–3631CrossRefPubMedGoogle Scholar
  14. Marson A, Foreman R, Chevalier B, Bilodeau S, Kahn M, Young RA, Jaenisch R (2008) Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell 3:132–135CrossRefPubMedGoogle Scholar
  15. McKinnon T, Ma H, Hasegawa K, Kahn M (2009) Trophectoderm differentiation in mouse preimplantation embryos involves Wnt signaling and a switch to the transcriptional coactivator p300. In ISSCR Annual Meeting, Barcelona, SpainGoogle Scholar
  16. McMillan M, Kahn M (2005) Investigating Wnt signaling: a chemogenomic safari. Drug Discov Today 10:1467–1474CrossRefPubMedGoogle Scholar
  17. Miyabayashi T, Teo JL, Yamamoto M, McMillan M, Nguyen C, Kahn M (2007) Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency. Proc Natl Acad Sci U S A 104:5668–5673CrossRefPubMedGoogle Scholar
  18. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Scholer H, Smith A (1998) Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct 4. Cell 95:379–391CrossRefPubMedGoogle Scholar
  19. Odorico JS, Kaufman DS, Thomson JA (2001) Multilineage differentiation from human embryonic stem cell lines. Stem Cells 19:193–204CrossRefPubMedGoogle Scholar
  20. Otero JJ, Fu W, Kan L, Cuadra AE, Kessler JA (2004) Beta-catenin signaling is required for neural differentiation of embryonic stem cells. Development 131:3545–3557CrossRefPubMedGoogle Scholar
  21. Radtke F, Clevers H (2005) Self-renewal and cancer of the gut: two sides of a coin. Science 307:1904–1909CrossRefPubMedGoogle Scholar
  22. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111CrossRefPubMedGoogle Scholar
  23. Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH (2004) Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10:55–63CrossRefPubMedGoogle Scholar
  24. Taupin P (2006) Stroke-induced neurogenesis: physiopathology and mechanisms. Curr Neurovasc Res 3:67–72CrossRefPubMedGoogle Scholar
  25. Teo JL, Ma H, Nguyen C, Lam C, Kahn M (2005) Specific inhibition of CBP/beta-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation. Proc Natl Acad Sci U S A 102:12171–12176CrossRefPubMedGoogle Scholar
  26. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147CrossRefPubMedGoogle Scholar
  27. Warburton D, Perin L, Defilippo R, Bellusci S, Shi W, Driscoll B (2008) Stem/progenitor cells in lung development, injury repair, and regeneration. Proc Am Thorac Soc 5:703–706CrossRefPubMedGoogle Scholar
  28. Xu Y, Shi Y, Ding S (2008) A chemical approach to stem-cell biology and regenerative medicine. Nature 453:338–344CrossRefPubMedGoogle Scholar
  29. Yamada T, Takaoka AS, Naishiro Y, Hayashi R, Maruyama K, Maesawa C, Ochiai A, Hirohashi S (2000) Transactivation of the multidrug resistance 1 gene by T-cell factor 4/beta-catenin ­complex in early colorectal carcinogenesis. Cancer Res 60:4761–4766PubMedGoogle Scholar
  30. Yamada T, Mori Y, Hayashi R, Takada M, Ino Y, Naishiro Y, Kondo T, Hirohashi S (2003) Suppression of intestinal polyposis in Mdr1-deficient ApcMin/+ mice. Cancer Res 63:895–901PubMedGoogle Scholar
  31. Yamanaka S (2009) A fresh look at iPS cells. Cell 137:13–17CrossRefPubMedGoogle Scholar
  32. Zechner D, Fujita Y, Hulsken J, Muller T, Walther I, Taketo MM, Crenshaw EB III, Birchmeier W, Birchmeier C (2003) beta-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev Biol 258:406–418CrossRefPubMedGoogle Scholar
  33. Zhang M, Rosen JM (2006) Stem cells in the etiology and treatment of cancer. Curr Opin Genet Dev 16:60–64CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Philipp C. Manegold
  • Jia-Ling Teo
  • Michael Kahn
    • 1
    • 2
    • 3
  1. 1.Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USCUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Department of Biochemistry and Molecular Biology Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  3. 3.Department of Molecular Pharmacology and ToxicologyUniversity of Southern CaliforniaLos AngelesUSA

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