Specific and combinatorial roles of GATA factors during organogenesis

Abstract

GATA4, GATA5, and GATA6 belong to a small family of conserved zinc finger transcription factors, and play critical roles in the development of the intestinal and cardiovascular systems. Throughout embryonic development their overlapping expression patterns suggests potential functional redundancies. However, deficiency in any one of the three factors leads to distinct heart and gut phenotypes, demonstrating also specific roles for each factor. My goal is to understand the specificity and the redundancy between GATA factors during organogenesis. First, I generated a murine embryonic stem (ES) cell line capable of induced expression of GATA4. I show that GATA4 expression is sufficient to enhance the generation of cardiomyocytes, and that this occurs through activation of an unknown secreted factor. In a complementary approach I use loss-of-function strategies in zebrafish, in which I first describe the requirement of Gata4 for late cardiac morphogenesis. I also show a role of Gata4 in the development of endoderm derivatives (gut, liver, and pancreas) as well as in the ectoderm derived lateral line system. Additionally, I targeted specific combinations of GATA factors. While embryos deficient in any one GATA factor display a distinct cardiac phenotype, I discovered that those depleted for both GATA5 and GATA6 are heartless, lacking completely cardiac progenitors. Using this approach I also described essential functions for combinations of GATA factors in liver and other endoderm derived organs. Therefore, I show that GATA4 is sufficient to induce indirectly cardiogenesis, while together, GATA5 and GATA6 are essential for cardiomyocyte specification. The ability to define the transcriptional network essential for cardiogenesis, and to enhance this process from ES cells may have clinical significance for treating diseased or failing heart tissue. Similar approaches may be relevant for other tissues, including liver and pancreas.