GATA transcription factors integrate Wnt signalling during heart development

Abstract

Cardiogenesis is inhibited by canonical Wnt/β-catenin signalling and stimulated by non-canonical Wnt11/JNK signalling, but how these two signalling pathways crosstalk is currently unknown. Here, we show that Wnt/β-catenin signalling restricts cardiogenesis via inhibition of GATA gene expression, as experimentally reinstating GATA function overrides β-catenin-mediated inhibition and restores cardiogenesis. Furthermore, we show that GATA transcription factors in turn directly regulate Wnt11 gene expression, and that Wnt11 is required to a significant degree for mediating the cardiogenesis-promoting function of GATA transcription factors. These results demonstrate that GATA factors occupy a central position between canonical and non-canonical Wnt signalling in regulating heart muscle formation.

Different requirements for GATA factors in cardiogenesis are mediated by non‐canonical Wnt signaling

“…Activation of Wnt11b is implicated in early cardiogenesis, since Wnt11b induces expression of cardiogenic markers such as Nkx2-5 and GATA4, as well as differentiation into beating cardiomyocyte tissue (Eisenberg and Eisenberg, 1999;Pandur et al, 2002). Furthermore, we have shown that, in turn, GATA4 and 6 induce Wnt11b gene expression directly, suggesting a possible regulatory loop between GATA factors and Wnt signaling molecules (Afouda et al, 2008).…”

“…In Xenopus, GATA4 is sufficient for driving not only induction of cardiac marker gene expression, but differentiation of beating tissue as well (Latinkic et al, 2003;Afouda et al, 2008). Recent studies in mouse have confirmed the importance of this factor and show that GATA4 is among three factors (GATA4, Tbx5, and Baf60c) that together are sufficient for transdifferentiation of non-cardiogenic mesoderm into beating cardiomyocytes (Takeuchi and Bruneau, 2009).…”

“…GATA proteins are transcription factors, which regulate diverse processes during embryogenesis and in adults (Patient and McGhee, 2002). The GATA4, 5, and 6 genes are all important in vertebrates for endoderm formation (Weber et al, 2000;Afouda et al, 2005) and are central regulators of heart development (Gove et al, 1997;Reiter et al, 1999;Peterkin et al, 2003Peterkin et al, , 2007Holtzinger and Evans, 2005;Afouda et al, 2008;Haworth et al, 2008;Takeuchi and Bruneau, 2009). They have overlapping spatial and temporal expression patterns and regulate cardiomyogenesis in a partially redundant manner (Holtzinger and Evans, 2007;Peterkin et al, 2007).…”

“…They have overlapping spatial and temporal expression patterns and regulate cardiomyogenesis in a partially redundant manner (Holtzinger and Evans, 2007;Peterkin et al, 2007). In addition, recent studies have provided evidence that they regulate each other (Afouda et al, 2005(Afouda et al, , 2008. It is, therefore, challenging to dissect the specific contribution different individual GATA factors make to cardiogenesis.…”

“…Wnt genes are among the non-cellautonomous targets of GATA factors (Alexandrovich et al, 2006;Afouda et al, 2008). The so-called canonical pathway involves b-catenin (Hoppler and Kavanagh, 2007); alternative, b-catenin-independent pathways are known as non-canonical pathways, one of which involves rho-GTPase, cdc42, and PKCd and may result in activation of Jun N-terminal Kinase (JNK) (Eisenberg and Eisenberg, 2006).…”