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Nf1 has an essential role in endothelial cells

Nature Genetics volume 33, pages 7579 (2003) | Download Citation



Neurofibromatosis type 1 (NF1) or von Recklinghausen neurofibromatosis is a genetic disorder that occurs in 1 of 4000 births and is characterized by benign and malignant tumors. Cardiovascular defects also contribute to NF1, though the pathogenesis is still unclear. Deficiency in neurofibromin (encoded by Nf1) in mice results in mid-embryonic lethality owing to cardiac abnormalities previously thought to be secondary to cardiac neural-crest defects. Using tissue-specific gene inactivation, we show that endothelial-specific inactivation of Nf1 recapitulates key aspects of the complete null phenotype, including multiple cardiovascular abnormalities involving the endocardial cushions and myocardium. This phenotype is associated with an elevated level of ras signaling in Nf1−/− endothelial cells and greater nuclear localization of the transcription factor Nfatc1. Inactivation of Nf1 in the neural crest does not cause cardiac defects but results in tumors of neural-crest origin resembling those seen in humans with NF1. These results establish a new and essential role for Nf1 in endothelial cells and confirm the requirement for neurofibromin in the neural crest.

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We are grateful to M. Yanagisawa for providing Tek–cre mice; B. Zhou for providing the Nfatc1 expression plasmid; L. Rorke for reviewing pathologic specimens; and M. Weiss, C. Thompson, C. Simon, E. Morrisey, M. Kahn and members of J.A.E.'s laboratory for critically reading the manuscript and for helpful discussions. This work was supported by grants from the WW Smith Foundation, the American Heart Association and the US National Institutes of Health to J.A.E. L.F.P. is supported by grants from the US National Institute of Neurological Disorders and Stroke and the US Department of Defense. A.D.G. is supported by the Department of Cell and Developmental Biology predoctoral training grant from the US National Institutes of Health. Y.Z. is a recipient of a Young Investigator Award from the National Neurofibromatosis Foundation.

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Author notes

    • Aaron D. Gitler
    •  & Yuan Zhu

    These authors contributed equally to this work.


  1. Department of Medicine, Cardiology Division, University of Pennsylvania Health System, 954 BRB II/III, 421 Curie Blvd., Philadelphia, Pennsylvania 19104, USA.

    • Aaron D. Gitler
    • , Fraz A. Ismat
    • , Min Min Lu
    •  & Jonathan A. Epstein
  2. Department of Cell and Developmental Biology, University of Pennsylvania Health System, 954 BRB II/III, 421 Curie Blvd., Philadelphia, Pennsylvania 19104, USA.

    • Aaron D. Gitler
    •  & Jonathan A. Epstein
  3. Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.

    • Yuan Zhu
    •  & Luis F. Parada
  4. Department of Pediatrics, Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Fraz A. Ismat
  5. Department of Developmental Genetics, Kumamoto University School of Medicine, Kuhonji, Kumamoto, Japan.

    • Yasutaka Yamauchi


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The authors declare no competing financial interests.

Corresponding author

Correspondence to Jonathan A. Epstein.

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