Wnt/beta-catenin signalling regulates cardiomyogenesis via GATA transcription factors.

A functioning heart muscle is required continuously throughout life. During embryonic development the heart muscle tissue differentiates from mesoderm that has heart-forming potential. Heart-forming potential in the embryonic mesoderm is regulated by pro-cardiogenic transcription factors, such as members of the GATA and NK-2 transcription factor families. Subsequent heart muscle differentiation involves the expression of cytoskeletal proteins, including myosins and troponins. Different Wnt signalling pathways have various functions in heart development. So-called 'canonical' (Wnt/beta-catenin-mediated) signalling has a conserved role in vertebrate heart development, regulating and restricting heart development and subsequent heart muscle differentiation. Here we investigated the way in which Wnt/beta-catenin signalling functionally interacts with the GATA family of pro-cardiogenic transcription factors to regulate subsequent heart muscle differentiation. We used whole Xenopus embryos as an accessible experimental model system for vertebrate heart development. Our experiments confirmed that activation of Wnt signalling results in reduced gata gene expression, as well as reduced gene expression of other pro-cardiogenic transcription factors and heart muscle differentiation markers. Remarkably, we discovered that when GATA function is experimentally restored, the expression of other pro-cardiogenic transcription factors and heart muscle differentiation markers is rescued. These findings, obtained from whole-embryo experiments, show that Wnt signalling regulates heart development at the level of GATA factors, confirming earlier results from tissue-culture experiments. Furthermore, our rescue experiments in Xenopus embryos revealed differences in functional activity between the various GATA transcription factors involved in heart development. We discovered that GATA4 is more efficient at reinstating the gene expression of other pro-cardiogenic transcription factors, whereas GATA6 is more potent at promoting the expression of genes associated with terminal heart muscle differentiation. In conclusion, our findings show that the inhibition of heart development by Wnt/beta-catenin signalling during organogenesis is mediated by the loss of expression of GATA pro-cardiogenic transcription factors and reveal functional differences between those GATA factors in heart development.