Cardiac chamber morphogenesis requires the coordinated growth of both cardiac muscle and endocardial cell lineages. Paracrine growth factors may modulate the coordinated cellular specification and differentiation during cardiac chamber morphogenesis, as suggested by the essential role of endothelial-derived growth factors, neuregulin-1, and insulin-like growth factor-I. Using the whole mouse embryo culture system for delivery of diffusible factors 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 insulin-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 cardiomyocytes, combined neuregulin-1 and insulin-like growth factor-I also had a synergistic effect to promote DNA synthesis and cellular growth, which were prevented by wortmannin, an inhibitor of phosphatidylinositol 3-kinase. Adenoviral delivery of dominant negative Rac1, which acts downstream of phosphatidylinositol 3-kinase, blocked the effect of combined neuregulin-1/insulin-like growth factor-I treatment. These studies support the concept that the interaction of neuregulin-1 and insulin-like growth factor-I pathways plays an important role in coordinating cardiac chamber morphogenesis and may occur through convergent activation of phosphatidylinositol 3-kinase.The formation, maturation, and septation of distinct cardiac chambers during heart development may require the interplay of signals between myocardial and endocardial cell lineages (1, 2). These distinct cell types present in the cardiogenic mesoderm will give rise to the double-layered heart tube, with myocardial cells forming the outer layer and endocardial cells forming the inner layer (3, 4). Within the looped cardiac tube, positional signals in the ventricular segment induce specific maturational steps in ventricular muscle cells, including trabeculation, expansion of the ventricular compact zone and atrioventricular cushions, and development of the interventricular septum. Another set of cues leads to the generation of cushion mesenchyme derived from endocardial cells, which contributes to septation of the conotruncus and outflow tract and remodeling of the atrioventricular canal, which ultimately separates the atrial and ventricular chambers (1, 2, 5). It has been previously shown by in vitro assay systems that cushion formation depends on extracellular matrix, and signals emanating from the adjacent cardiomyocytes (5, 6). However, the potential effect of endocardial-derived signals in cushion morphogenesis has not yet been explored. The maturational steps in ventricular muscle and endocardial cells might be mutually coordinated. However, the interplaying signals involved at these different steps of the developing embryonic heart are still unknown.Recent studies from ta...
