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

• Published in: Nature (London) 1998-03, Vol.392 (6672), p.182-186
• Main Authors: de la Pompa, José Luis, Timmerman, Luika A., Takimoto, Hiroaki, Yoshida, Hiroki, Elia, Andrew J., Samper, Enrique, Potter, Julia, Wakeham, Andrew, Marengere, Luc, Langille, B. Lowell, Crabtree, Gerald R., Mak, Tak W.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Birth defects; Calcineurin - metabolism; Calcineurin Inhibitors; Calcium; Calcium - metabolism; Cardiovascular diseases; Cell Line; Culture Techniques; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Endothelium - metabolism; Fetal Death; Fundamental and applied biological sciences. Psychology; Gene Targeting; Genes; Genetics; Heart; Heart Septal Defects - embryology; Heart Septum - embryology; Heart Valves - abnormalities; Heart Valves - embryology; Humanities and Social Sciences; Humans; Immune response; letter; Lymphocytes; Mice; Mice, Inbred C57BL; Morphogenesis - physiology; multidisciplinary; Mutagenesis; NFATC Transcription Factors; Nuclear Proteins; Rodents; Science; Science (multidisciplinary); Signal Transduction; Tacrolimus - pharmacology; Transcription Factors - genetics; Transcription Factors - physiology; Vertebrates: cardiovascular system
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/32419

In lymphocytes, the expression of early immune response genes is regulated by NF-AT transcription factors 1 , 2 which translocate to the nucleus after dephosphorylation by the Ca 2+ -dependent phosphatase, calcineurin 3 . 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 4 . Treatment of wild-type embryos with FK506, a specific calcineurin inhibitor 5 , prevents nuclear localization of NF-ATc. These data indicate that the Ca 2+ /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.