Synergistic roles of neuregulin-1 and insulin-like growth factor-I in activation of the phosphatidylinositol 3-kinase pathway and cardiac chamber morphogenesis

Cardiac chamber morphogenesis requires the coordinated growth of both cardi ac muscle and endocardial cell lineages. Paracrine growth factors may modul ate the coordinated cellular specification and differentiation during cardi ac chamber morphogenesis, as suggested by the essential role of endothelial -derived growth factors, neuregulin-1, and insulin-like growth factor-I. Us ing the whole mouse embryo culture system for delivery of diffusible factor s into the cardiac chamber, neuregulin-1 was shown to promote trabeculation of the ventricular wall. Another factor, insulin-like growth factor-I, had no apparent effect by itself. Combined treatment with neuregulin-1 and ins ulin-like growth factor-I strongly induced DNA synthesis of cardiomyocytes and expansion of both the ventricular compact zone and the atrioventricular cushions leading to chamber growth and maturation. In cultured cardiomyocy tes, combined neuregulin-1 and insulin-like growth factor-I also had a syne rgistic effect to promote DNA synthesis and cellular growth, which were pre vented by wortmannin, an inhibitor of phosphatidylinositol 3-kinase, Adenov iral delivery of dominant negative Rad, which acts downstream of phosphatid ylinositol S-kinase, blocked the effect of combined neuregulin-1/insulin-li ke growth factor-I treatment. These studies support the concept that the in teraction of neuregulin-1 and insulin-like growth factor-I pathways plays a n important role in coordinating cardiac chamber morphogenesis and may occu r through convergent activation of phosphatidylinositol 3-kinase.