ROLE OF THE NF-ATC TRANSCRIPTION FACTOR IN MORPHOGENESIS OF CARDIAC VALVES AND SEPTUM

In lymphocytes, the expression of early immune response genes is regul ated by NF-AT transcription factors(1,2) which translocate to the nucl eus after dephosphorylation by the Ca2+-dependent phosphatase, calcine urin(3). We report here that mice bearing a disruption in the NF-ATc g ene fail to develop normal cardiac valves and septa and die of circula tory failure before day 14.5 of development. NF-ATc is first expressed in the heart at day 7.5, and is restricted to the endocardium, a spec ialized endothelium that gives rise to the valves and septum. Within t he endocardium, specific inductive events appear to activate NF-ATc: i t is localized to the nucleus only in endocardial cells that are adjac ent to the interface with the cardiac jelly and myocardium, which are thought to give the inductive stimulus to the valve primordia(4). Trea tment of wild-type embryos with FK506, a specific calcineurin inhibito r(5), prevents nuclear localization of NF-ATc. These data indicate tha t the Ca2+/calcineurin/NF-ATc signalling pathway is essential for norm al cardiac valve and septum morphogenesis; hence, NF-ATc and its regul atory pathways are candidates for genetic defects underlying congenita l human heart disease.