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

José Luis de la Pompa, Luika A. Timmerman, Hiroaki Takimoto, Hiroki Yoshida, Andrew J. Elia, Enrique Samper, Julia Potter, Andrew Wakeham, Luc Marengere, B. Lowell Langille, Gerald R. Crabtree and Tak W. Mak ()
Additional contact information
José Luis de la Pompa: Amgen Institute, Ontario Cancer Institute, University of Toronto
Luika A. Timmerman: Stanford University Medical School Howard Hughes Medical Institute
Hiroaki Takimoto: Amgen Institute, Ontario Cancer Institute, University of Toronto
Hiroki Yoshida: Amgen Institute, Ontario Cancer Institute, University of Toronto
Andrew J. Elia: Amgen Institute, Ontario Cancer Institute, University of Toronto
Enrique Samper: Amgen Institute, Ontario Cancer Institute, University of Toronto
Julia Potter: Amgen Institute, Ontario Cancer Institute, University of Toronto
Andrew Wakeham: Amgen Institute, Ontario Cancer Institute, University of Toronto
Luc Marengere: Amgen Institute, Ontario Cancer Institute, University of Toronto
B. Lowell Langille: Max Bell Research Centre
Gerald R. Crabtree: Stanford University Medical School Howard Hughes Medical Institute
Tak W. Mak: Amgen Institute, Ontario Cancer Institute, University of Toronto

Nature, 1998, vol. 392, issue 6672, 182-186

Abstract: Abstract In lymphocytes, the expression of early immune response genes is regulated by NF-AT transcription factors1,2 which translocate to the nucleus after dephosphorylation by the Ca2+-dependent phosphatase, calcineurin3. 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 primordia4. Treatment of wild-type embryos with FK506, a specific calcineurin inhibitor5, 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.

Date: 1998
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DOI: 10.1038/32419

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