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The transcription factor NF-ATc is essential for cardiac valve formation

Abstract

Nuclear factor of activated T cells (NF-AT) is the name of a family of four related transcription factors that may be needed for cytokine gene expression in activated lymphocytes1,2,3,4. Here we report that mice with a targeted disruption of the NF-ATc gene show an unexpected and dramatic defect in cardiac morphogenesis, with selective absence of the aortic and pulmonary valves, leading to death in utero from congestive heart failure at days 13.5–17.5 of gestation. In contrast, tricuspid and mitral valve morphogenesis is normal. NF-ATc is the first transcription factor known to be expressed only in the endothelial cells of the heart. As in T cells, nuclear translocation of NF-ATc in cardiac endothelial cells is controlled by the calcium-regulated phosphatase calcineurin5,6: NF-ATc remains cytoplasmic in normal embryos cultured with cyclosporin A, an inhibitor of calcineurin. Abnormal development of the cardiac valves and septae is the most frequent form of birth defect, yet few molecular regulators of valve formation are known. Our results indicate that NF-ATc may play a critical role in signal-transduction processes required for normal cardiac valve formation.

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Figure 1: Targeted disruption of the murine NF-ATc gene.
Figure 2: Histological analysis of e14.5 wild-type and NF-ATc-mutant embryos from line 141.
Figure 3: Histological analysis of e14.5 and e11.5 wild-type and NF-ATc−/− embryos from line 141.
Figure 4: Developmental, temporal, and spatial expression of NF-ATc.

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Acknowledgements

We thank G. Crabtree and L. Timmerman for NF-AT reagents; E. Robertson for help in embryo dissection and preparation; C. Freedman for preparation of the mansucript; and P. Bannerman and T. Oliver of the Children's Hospital of Philadelphia and University of Pennsylvania Cancer Center Confocal Microscopy Core for advice and assistance. This work was supported by grants for the NIH (L.H.G. and H.S.B.), a National Science Foundation Fellowship (A.M.R.) and a gift from the G. Harold and Leila Y. Mathers Charitable Foundation (L.H.G.). M.J.G. is a scholar of the Leukemia Society of America. H.S.B. is an Established Investigator of the American Heart Association.

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Correspondence to Laurie H. Glimcher.

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Ranger, A., Grusby, M., Hodge, M. et al. The transcription factor NF-ATc is essential for cardiac valve formation. Nature 392, 186–190 (1998). https://doi.org/10.1038/32426

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