Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum

Abstract

In lymphocytes, the expression of early immune response genes is regulated by NF-AT transcription factors which translocate to the nucleus after dephosphorylation by the Ca2+-dependent phosphatase, calcineurin. We report here that mice bearing a disruption in the NF-ATc gene fail to develop normal cardiac valves and septa and die of circulatory 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 specialized endothelium that gives rise to the valves and septum. Within the endocardium, specific inductive events appear to activate NF-ATc: it is localized to the nucleus only in endocardial cells that are adjacent to the interface with the cardiac jelly and myocardium, which are thought to give the inductive stimulus to the valve primordia. Treatment of wild-type embryos with FK506, a specific calcineurin inhibitor, prevents nuclear localization of NF-ATc. These data indicate that the Ca2+/calcineurin/NF-ATc signalling pathway is essential for normal cardiac valve and septum morphogenesis; hence, NF-ATc and its regulatory pathways are candidates for genetic defects underlying congenital human heart disease.

Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation

“…First, mRor2 is required for cardiac septal formation. Recent genetic analyses have revealed that many regulatory molecules, including growth factors, receptors and transcription factors, are involved in the development of the heart (Nagasawa et al 1996;Basson et al 1997;Li et al 1997;Tessarollo et al 1997;de la Pompa et al 1998;Ranger et al 1998;Schott et al 1998;Tachibana et al 1998; reviewed in Burn & Goodship 1996;Lyons 1996;Rossant 1996;Barinaga 1998), although in general their roles are not restricted to septal formation. Interestingly, defects of the cardiac septum have been, thus far, the major abnormality observed in the cardio-vascular system of mRor2 À/À mice.…”

Calcineurin signaling in avian cardiovascular development

“…In the developing cardiovascular system, calcineurin signaling is required for cardiomyocyte maturation and function as well as early vascular development. During heart chamber formation, calcineurin signaling and NFATc1 function are required for valvuloseptal development, and calcineurin signaling also has been implicated in compaction of the ventricular myocardium (de la Pompa et al, 1998;Ranger et al, 1998;Shou et al, 1998;Guo et al, 2002). In the adult heart, calcineurin signaling has a central role in cardiac hypertrophy (Bueno et al, 2002b).…”

“…Targeted mutagenesis of specific NFAT family members revealed additional requirements for calcineurin/NFAT signaling in the developing heart. Loss of NFATc1 results in embryonic lethality due to defects in cardiac valvuloseptal development (de la Pompa et al, 1998;Ranger et al, 1998). Embryos lacking both NFATc3 and NFATc4 have embryonic lethal cardiac metabolic defects and exhibit abnormalities in vascular maturation (Graef et al, 2001a;Bushdid et al, 2003).…”

Nuclear factor of activated T (NFAT) cells activity within CD4+ T cells is influenced by activation status and tissue localisation

“…Four members of the family have been identified, NFATc1, NFATc2, NFATc3 and NFATc4. NFATc1 and NFATc2 are the predominant members in T cells, but they are also expressed in a large variety of tissues including heart, neurons, vascular cells, chondriocytes, and adipocytes [3][4][5][6][7].…”