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

Nature volume 392, pages 182–186 (1998)Cite this article

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.

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Figure 1: Targeting of the NF-ATc gene.
Figure 2: NF-ATc expression is restricted to the endocardium, outflow tract and cardiac valves.
Figure 3: Active NF-ATc is expressed in a subset of endothelial cells lining the endocardial cushions and valves.
Figure 4: Cardiac valves and ventricular septum defects in NF-ATc3 mutant embryos.
Figure 5: FK506 treatment blocks NF-ATc nuclear import in the endocardium.

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Acknowledgements

L.A.T., H.T. and H.Y. contributed equally to this work. We thank C. Sirard, J. Cross, V. Stambolic and R. Hakem for critical reading of this manuscript, and H. Clever for the Sox-4 probe.

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Authors and Affiliations

  1. the and Departments of Medical Biophysics and Immunology, Amgen Institute, Ontario Cancer Institute, University of Toronto, 620 University Avenue, Toronto, M5G 2C1, Ontari, Canada

    José Luis de la Pompa, Hiroaki Takimoto, Hiroki Yoshida, Andrew J. Elia, Enrique Samper, Julia Potter, Andrew Wakeham, Luc Marengere & Tak W. Mak

  2. the Department of Developmental Biology, Stanford University Medical School Howard Hughes Medical Institute, 300 Pasteur Drive, Stanford, 94305, California, USA

    Luika A. Timmerman & Gerald R. Crabtree

  3. Toronto General Division, Max Bell Research Centre, 200 Elizabeth Street, Toronto, M5G 2C4, Ontario, Canada

    B. Lowell Langille

  4. Department of Pathology, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    B. Lowell Langille

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  1. José Luis de la Pompa
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Correspondence to Tak W. Mak.

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de la Pompa, J., Timmerman, L., Takimoto, H. et al. Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature 392, 182–186 (1998). https://doi.org/10.1038/32419

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