Saito H, Yoshida T, Yamazaki H, Suzuki N
Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, Edobashi, Tsu, Mie, Japan.
Oncogene. 2007 Jul 12;26(32):4714-9. doi: 10.1038/sj.onc.1210250. Epub 2007 Jan 22.
Human clinical neurofibromatosis type 1 (NF1) and type 2 (NF2) result from mutations and inactivation of neurofibromin and merlin genes, respectively, which negatively regulate Ras pathways. To evaluate the contribution of N-Ras activity to the development of NF, we generated a novel transgenic mouse expressing oncogenic N-ras specifically in central nerve cells, neural crest-derived cells and lens epithelial cells. Soon after birth, the mouse skin showed hyperpigmentation of the epidermis and melanin-laden macrophages in the dermis, as observed in the café-au-lait spots of human cases. At 3 months of age, all the mice had neurofibromas in the skin and neurofibroma-like tumors with structure similar to Wagner-Meissner bodies in the adrenal medulla. At 4 months of age, all the mice developed subcapsular cataract. In the 5th month, some developed protruding dermal neurofibromas involving subcutaneous fat. However, plexiform neurofibroma, schwannoma, astrocytoma and pheochromocytoma were not observed in the mice, suggesting a requirement for signal(s) other than the activated N-Ras pathway to induce these tumors. Thus, the activated N-Ras signal may be a main pathway for the development of the disease phenotypes characteristic of NF.
人类临床1型神经纤维瘤病（NF1）和2型神经纤维瘤病（NF2）分别由神经纤维瘤蛋白和默林基因的突变和失活引起，这两种基因对Ras通路起负调控作用。为了评估N-Ras活性对神经纤维瘤病（NF）发展的作用，我们构建了一种新型转基因小鼠，其在中枢神经细胞、神经嵴衍生细胞和晶状体上皮细胞中特异性表达致癌性N-ras。出生后不久，小鼠皮肤出现表皮色素沉着过度以及真皮中充满黑色素的巨噬细胞，这与人类病例的咖啡斑中观察到的情况一致。在3个月大时，所有小鼠的皮肤都出现了神经纤维瘤，并且在肾上腺髓质中出现了结构类似于瓦格纳-迈斯纳小体的神经纤维瘤样肿瘤。在4个月大时，所有小鼠都出现了囊下白内障。在第5个月时，一些小鼠出现了累及皮下脂肪的突出性皮肤神经纤维瘤。然而，在这些小鼠中未观察到丛状神经纤维瘤、神经鞘瘤、星形细胞瘤和嗜铬细胞瘤，这表明诱导这些肿瘤需要激活的N-Ras通路以外的信号。因此，激活的N-Ras信号可能是NF特征性疾病表型发展的主要途径。
