Cell death and differentiation in the development of the endocardial cushion of the embryonic heart

The transformation of the endocardial cushion into valves and septa is a critical step in cardiac morphogenesis as it initiates the development of the four-chambered heart. This transformation results from a region-specific balance between cellular proliferation, apoptosis, and differentiation. The development of the form and structure of the endocardial cushion is accompanied by precise patterns of abundant cell death having the morphological features of programmed cell death (apoptosis), which plays an important role in the elimination of redundant cells and in changes of phenotypic composition during histogenesis. Apoptosis is an essential process in morphogenesis as it balances mitosis in renewing tissues. It is controlled by one or more genetic programs that kill the targeted cell. However, the causes, role, and regulation of apoptosis in the developing endocardial cushion still remain to be determined. The clarification of the role of the apoptosis regulatory genes constitutes a major task in future studies of cell death in the developing heart. This new molecular histology of heart development awaits further experiments to clarify the interactive mechanisms that act to ensure the sculpting of the endocardial cushion into valves and septa by determining the size of the cushion cell populations. The relation between the expression of different factors and the modifications of the cushion region during cardiac development are reviewed. In addition, we review and summarize information on molecules identified in our experiments that imply the activity of a number of essential genes coinciding with the key steps in generating the overall architecture of the heart. We correlate their temporal and spatial expression with their proposed roles.