Gitler Aaron D, Zhu Yuan, Ismat Fraz A, Lu Min Min, Yamauchi Yasutaka, Parada Luis F, Epstein Jonathan A
Department of Medicine, Cardiology Division, University of Pennsylvania Health System, 954 BRB II/III, 421 Curie Blvd., Philadelphia, Pennsylvania 19104, USA.
Nat Genet. 2003 Jan;33(1):75-9. doi: 10.1038/ng1059. Epub 2002 Dec 9.
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.
1型神经纤维瘤病（NF1）或冯雷克林霍增氏神经纤维瘤病是一种遗传性疾病，发病率为4000分之一，其特征为良性和恶性肿瘤。心血管缺陷也与NF1有关，但其发病机制仍不清楚。小鼠中神经纤维瘤蛋白（由Nf1编码）的缺乏会导致胚胎中期死亡，原因是先前认为是继发于心脏神经嵴缺陷的心脏异常。通过组织特异性基因失活，我们发现Nf1在内皮细胞中的特异性失活概括了完全缺失表型的关键方面，包括涉及心内膜垫和心肌的多种心血管异常。这种表型与Nf1（-/-）内皮细胞中ras信号水平升高以及转录因子Nfatc1的核定位增加有关。神经嵴中Nf1的失活不会导致心脏缺陷，但会导致神经嵴起源的肿瘤，类似于NF1患者中所见的肿瘤。这些结果确立了Nf1在内皮细胞中的新的重要作用，并证实了神经嵴中神经纤维瘤蛋白的必要性。
