Nature Genetics
33, 75 - 79 (2002)
Published online: 9 December 2002; | doi:10.1038/ng1059
Nf1 has an essential role in endothelial cellsAaron D. Gitler1, 2, 6, Yuan Zhu3, 6, Fraz A. Ismat1, 4, Min Min Lu1, Yasutaka Yamauchi5, Luis F. Parada3
& Jonathan A. Epstein1, 21
Department of Medicine, Cardiology Division, University of Pennsylvania Health System, 954 BRB II/III, 421 Curie Blvd., Philadelphia, Pennsylvania 19104, USA. 2
Department of Cell and Developmental Biology, University of Pennsylvania Health System, 954 BRB II/III, 421 Curie Blvd., Philadelphia, Pennsylvania 19104, USA. 3
Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA. 4
Department of Pediatrics, Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 5
Department of Developmental Genetics, Kumamoto University School of Medicine, Kuhonji, Kumamoto, Japan. 6
These authors contributed equally to this work.
Correspondence should be addressed to Jonathan A. Epstein epsteinj@mail.med.upenn.eduNeurofibromatosis 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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