Nf1 has an essential role in endothelial cells
Nf1 has an essential role in endothelial cells
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DOI：
10.1038/ng1059
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发表时间：
2003-01-01
期刊：
影响因子：
30.8
通讯作者：
Epstein, JA
中科院分区：
文献类型：
--
作者：
Gitler, AD;Zhu, Y;Epstein, JA
1型神经纤维瘤病（NF 1）或von Recklinghausen神经纤维瘤病是一种遗传性疾病，每4000名新生儿中就有1名发生，其特征是良性和恶性肿瘤。心血管缺陷也会导致NF 1，尽管其发病机制仍不清楚。小鼠神经纤维蛋白（由Nf 1编码）的缺乏导致胚胎中期死亡，这是由于心脏异常，以前认为是继发于心脏神经嵴缺陷。使用组织特异性基因失活，我们表明，内皮细胞特异性失活的NF 1概括了关键方面的完全无效的表型，包括多种心血管异常，涉及内膜垫和心肌。这种表型与Nf 1（-/-）内皮细胞中ras信号水平升高和转录因子Nfatc 1更大的核定位相关。神经嵴中Nf 1的失活不会导致心脏缺陷，但会导致神经嵴起源的肿瘤，类似于在患有NF 1的人类中所见的肿瘤。这些结果建立了一个新的和必不可少的作用，NF 1在内皮细胞，并确认在神经嵴的神经纤维蛋白的要求。
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.