Regulation of avian cardiac myogenesis by activin/TGF beta and bone morphogenetic proteins

Previous studies have identified two signaling interactions regulating card iac myogenesis in avians, a hypoblast-derived signal acting on epiblast and mediated by activin or a related molecule and an endoderm-derived signal a cting on mesoderm and involving BMP-2. In this study, experiments were desi gned to investigate the temporal relationship between these signaling event s and the potential role of other TGF beta superfamily members in regulatin g early steps of heart muscle development. Sire find that while activin or TGF beta can potently induce cardiac myogenesis in pregastrula epiblast, th ey show no capacity to convert noncardiogenic mesoderm toward a myocardial phenotype. Conversely, BMP-2 or BMP-4, in combination with FGF-4, can readi ly induce cardiac myocyte formation in posterior mesoderm, but shows no cap acity to induce cardiac myogenesis in epiblast cells. Activin/TGF beta and BMP-2/BMP-4 therefore have distinct and reciprocal cardiac-inducing capacit ies that mimic the tissues in which they are expressed, the pregastrula hyp oblast and anterior lateral endoderm, respectively. Experiments with noggin and follistatin provide additional evidence indicating that BMP signaling lies downstream of an activin/TGF beta signal in the cardiac myogenesis pat hway. In contrast to the cardiogenic-inducing capacities of BMP-2/BMP-4 in mesoderm, however, we find that BMP-2 or BMP-4 inhibits cardiac myogenesis prior to stage 3, demonstrating multiple roles for BMPs in mesoderm inducti on. These and other published studies suggest a signaling cascade in which a hypoblast-derived activin/TGF beta signal is required prior to and during early stages of gastrulation, regulated both spatially and temporally by a n interplay between BMPs and their antagonists. Later cardiogenic signals a rising from endoderm, and perhaps transiently from ectoderm, and mediated i n part by BMPs, act on emerging mesoderm within cardiogenic regions to acti vate or enhance expression of cardiogenic genes such as GATA and cNkx famil y members, leading to cardiac myocyte differentiation. (C) 1998 Academic Pr ess.