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

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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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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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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