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Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis

Nature volume 418, pages 636–641 (2002)Cite this article

Abstract

Formation of the vertebrate heart requires a complex interplay of several temporally regulated signalling cascades1. In Xenopus laevis, cardiac specification occurs during gastrulation and requires signals from the dorsal lip and underlying endoderm2. Among known Xenopus Wnt genes, only Wnt-11 shows a spatiotemporal pattern of expression that correlates with cardiac specification, which indicates that Wnt-11 may be involved in heart development3,4. Here we show, through loss- and gain-of-function experiments, that XWnt-11 is required for heart formation in Xenopus embryos and is sufficient to induce a contractile phenotype in embryonic explants. Treating the mouse embryonic carcinoma stem cell line P19 with murine Wnt-11 conditioned medium triggers cardiogenesis, which indicates that the function of Wnt-11 in heart development has been conserved in higher vertebrates. XWnt-11 mediates this effect by non-canonical Wnt signalling, which is independent of β-catenin and involves protein kinase C and Jun amino-terminal kinase. Our results indicate that the cardiac developmental program requires non-canonical Wnt signal transduction.

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Figure 1: Inhibition of XWnt-11 signalling interferes with heart development.
Figure 2: XWnt-11 triggers early steps of cardiogenesis in pluripotent precursor cells by activating JNK.
Figure 3: XWnt-11 and formation of contractile tissue in embryonic explants.
Figure 4: Wnt-11 conditioned medium (CM) triggers cardiomyocyte formation in mouse P19 carcinoma cells.

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References

  1. Sucov, H. M. Molecular insights into cardiac development. Annu. Rev. Physiol. 60, 287–308 (1998)

    Article  CAS  PubMed  Google Scholar 

  2. Nascone, N. & Mercola, M. An inductive role for the endoderm in Xenopus cardiogenesis. Development 121, 515–523 (1995)

    CAS  PubMed  Google Scholar 

  3. Ku, M. & Melton, D. A. XWnt-11: a maternally expressed Xenopus wnt gene. Development 119, 1161–1173 (1993)

    CAS  PubMed  Google Scholar 

  4. Schroeder, K. E., Condic, M. L., Eisenberg, L. M. & Yost, H. Y. Spatially regulated translation in embryos: asymmetric expression of maternal Wnt-11 along the dorsal-ventral axis in Xenopus. Dev. Biol. 214, 288–297 (1999)

    Article  CAS  PubMed  Google Scholar 

  5. Tada, M. & Smith, J. C. XWnt11 is a target of Xenopus Brachyury: regulation of gastrulation movements via Dishevelled, but not through the canonical Wnt pathway. Development 127, 2227–2238 (2000)

    CAS  PubMed  Google Scholar 

  6. Miller, J. R., Hocking, A. M., Brown, J. D. & Moon, R. T. Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene 18, 7860–7872 (1999)

    Article  CAS  PubMed  Google Scholar 

  7. Djiane, A., Riou, J.-F., Umbhauer, M., Boucaut, J.-C. & Shi, D.-L. Role of frizzled 7 in the regulation of convergent extension movements during gastrulation in Xenopus laevis. Development 127, 3091–3100 (2000)

    CAS  PubMed  Google Scholar 

  8. Kühl, M., Sheldahl, L. C., Park, M., Miller, J. R. & Moon, R. T. The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet. 16, 279–283 (2000)

    Article  PubMed  Google Scholar 

  9. Marvin, M. J., Di Roco, G., Gardiner, A., Bush, S. M. & Lassar, A. B. Inhibition of Wnt activity induces heart formation from posterior mesoderm. Genes Dev. 15, 316–327 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schneider, V. A. & Mercola, M. Wnt antagonism initiates cardiogenesis in Xenopus laevis. Genes Dev. 15, 304–315 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kispert, A., Vainio, S., Shen, L., Rowitch, D. H. & McMahon, A. P. Proteoglycans are required for maintenance of Wnt-11 expression in the ureter tips. Development 122, 3627–3637 (1996)

    CAS  PubMed  Google Scholar 

  12. Eisenberg, C. A., Gourdie, R. G. & Eisenberg, L. M. Wnt-11 is expressed in early avian mesoderm and required for the differentiation of the quail mesoderm cell line QCE-6. Development 124, 525–536 (1997)

    CAS  PubMed  Google Scholar 

  13. Eisenberg, C. A. & Eisenberg, L. M. WNT11 promotes cardiac tissue formation of early mesoderm. Dev. Dyn. 216, 45–58 (1999)

    Article  CAS  PubMed  Google Scholar 

  14. Kühl, M., Sheldahl, L. C., Malbon, C. C. & Moon, R. T. Ca2+/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 (2000)

    Article  PubMed  Google Scholar 

  15. Tonissen, K. F., Drysdale, T. A., Lints, T. J., Harvey, R. P. & Krieg, P. A. XNkx-2.5, a Xenopus gene related to Nkx-2.5 and tinman: evidence for a conserved role in cardiac development. Dev. Biol. 162, 325–328 (1994)

    Article  CAS  PubMed  Google Scholar 

  16. Drysdale, T. A., Tonissen, K. F., Patterson, K. D., Crawford, M. J. & Krieg, P. A. Cardiac troponin I is a heart-specific marker in the Xenopus embryo: expression during abnormal heart morphogenesis. Dev. Biol. 165, 432–441 (1994)

    Article  CAS  PubMed  Google Scholar 

  17. Grunz, H. Change in the differentiation pattern of Xenopus laevis ectoderm by variation of the incubation time and concentration of vegetalizing factor. Roux's Arch. Dev. Biol. 192, 130–137 (1983)

    Article  Google Scholar 

  18. Sheldahl, L. C., Park, M., Malbon, C. C. & Moon, R. T. Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Curr. Biol. 9, 695–698 (1999)

    Article  CAS  PubMed  Google Scholar 

  19. Boutros, M. & Mlodzik, M. Dishevelled: at crossroads of divergent intracellular signaling pathways. Mech. Dev. 83, 27–37 (1999)

    Article  CAS  PubMed  Google Scholar 

  20. Yamanaka, H. et al. JNK functions in the non-canonical Wnt pathway to regulate convergent extension movements in vertebrates. EMBO Rep. 3, 69–75 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nishitoh, H. et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol. Cell. 2, 389–395 (1998)

    Article  CAS  PubMed  Google Scholar 

  22. De Windt, L. J., Lim, H. W., Haq, S., Force, T. & Molkentin, J. D. Calcineurin promotes protein kinase C and c-Jun NH2-terminal kinase activation in the heart. J. Biol. Chem. 275, 13571–13579 (2000)

    Article  CAS  PubMed  Google Scholar 

  23. Torres, M. A. et al. Activities of the wnt-1 class of secreted factors are antagonized by the wnt-5 A class and by a dominant negative cadherin in early Xenopus embryo. J. Cell Biol. 133, 1123–1137 (1996)

    Article  CAS  PubMed  Google Scholar 

  24. Kühl, M. et al. Antagonistic regulation of convergent extension movements by Wnt/β-catenin and Wnt/Ca2+ signalling. Mech. Dev. 106, 61–76 (2001)

    Article  PubMed  Google Scholar 

  25. Behrens, J. et al. Functional interaction of β–catenin and the architectural transcription factor LEF-1. Nature 382, 638–642 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Grepin, C., Nemer, G. & Nemer, M. Enhanced cardiogenesis in embryonic stem cells overexpressing the GATA-4 transcription factor. Development 124, 2387–2395 (1997)

    CAS  PubMed  Google Scholar 

  27. Bader, D., Masaki, T. & Fischman, D. A. Immunochemical analysis of myosin heavy chain during avian myogenesis in vivo and in vitro. J. Cell Biol. 95, 763–770 (1982)

    Article  CAS  PubMed  Google Scholar 

  28. Rudnicki, M. A. & McBurney, M. W. in Teratocarcinomas and Embryonic Stem Cells. A Practical Approach (ed. Robertson, E. J.) 19–49 (IRL, Oxford, 1987)

    Google Scholar 

  29. Pera, E. M. & DeRobertis, E. M. A direct screen for secreted proteins in Xenopus embryos identifies distinct activities for the Wnt antagonists crescent and Frzb-1. Mech. Dev. 96, 183–195 (2000)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R. T. Moon, A. McMahon, P. Krieg, K. Matsumoto, E. Pera, D. Kimelman, W. Birchmeier and A. Kispert for providing cDNA clones; A. Kispert for providing the Wnt-transfected NIH3T3 cells; D. Gradl for help with confocal imaging analyses; and T. Hollemann for help with video capturing.

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Authors and Affiliations

  1. Abt Entwicklungsbiochemie, Junior group SFB 271, Universität Göttingen, Humboldtallee 23, D-37073, Göttingen, Germany

    Petra Pandur, Matthias Läsche & Michael Kühl

  2. Abt Biochemie, Universität Ulm, Albert-Einstein-Allee-11, D-89081, Ulm, Germany

    Petra Pandur & Michael Kühl

  3. Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina, 29425, USA

    Leonard M. Eisenberg

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  1. Petra Pandur
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Correspondence to Michael Kühl.

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Pandur, P., Läsche, M., Eisenberg, L. et al. Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis. Nature 418, 636–641 (2002). https://doi.org/10.1038/nature00921

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