A mouse embryonic stem cell model of Schwann cell differentiation for studies of the role of neurofibromatosis type 1 in Schwann cell development and tumor formation
A mouse embryonic stem cell model of Schwann cell differentiation for studies of the role of neurofibromatosis type 1 in Schwann cell development and tumor formation
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DOI：
10.1002/glia.20534
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发表时间：
2007-08-15
期刊：
影响因子：
6.2
通讯作者：
Barald, Kate F.
中科院分区：
文献类型：
--
作者：
Roth, Therese M.;Ramamurthy, Poornapriya;Barald, Kate F.
神经纤维瘤病1型（NF1）基因是一种肿瘤抑制基因。神经纤维蛋白（NF1蛋白产物）的一个已知功能是加速Ras缓慢的内在GTPase活性，以增加无活性rasGDP的产生，对p21ras通路具有广泛的影响。常染色体显性遗传病NF1中神经纤维蛋白的缺失与周围神经系统肿瘤有关，特别是神经纤维瘤，这是一种良性病变，主要受影响的细胞类型是雪旺细胞（SC）。NF1是影响神经系统的最常见的癌症易感性综合征。我们已经开发了一种体外系统，用于将小鼠胚胎干细胞（mESC）分为NF1野生型（+P/+）、杂合型（+/-）或零型（-/-）分化为SC样细胞，以研究NF1在SC发育和肿瘤形成中的作用。这些mes生成的SC样细胞，无论其NF1状态如何，都表达与成熟阶段相关的SC标记物，包括髓磷脂蛋白。它们还支持并优先指导原代神经元的神经突生长。与NF1野生型相比，NF1缺失型和杂合型sc样细胞增殖速度加快；这种生长优势可以通过MAP激酶（Mek）抑制剂恢复到野生型水平。所有NF1型的mESC均可分化为神经元样细胞。这个新颖的模型系统为研究NF1在细胞生长和分化中的作用提供了一个理想的范例，NF1在具有不同水平的非转化或恶性神经纤维蛋白的细胞中受不同类型的细胞的影响。(C) 2007 Wiley-Liss, Inc。
The neurofibromatosis Type 1 (NF1) gene functions as a tumor suppressor gene. One known function of neurofibromin, the NF1 protein product, is to accelerate the slow intrinsic GTPase activity of Ras to increase the production of inactive rasGDP, with wide-ranging effects on p21ras pathways. Loss of neurofibromin in the autosomal dominant disorder NF1 is associated with tumors of the peripheral nervous system, particularly neurofibromas, benign lesions in which the major affected cell type is the Schwann cell (SC). NF1 is the most common cancer predisposition syndrome affecting the nervous system. We have developed an in vitro system for differentiating mouse embryonic stem cells (mESC) that are NF1 wild type (+P/+), heterozygous (+/-), or null (-/-) into SC-like cells to study the role of NF1 in SC development and tumor formation. These mES-generated SC-like cells, regardless of their NF1 status, express SC markers correlated with their stage of maturation, including myelin proteins. They also support and preferentially direct neurite outgrowth from primary neurons. NF1 null and heterozygous SC-like cells proliferate at an accelerated rate compared to NF1 wild type; this growth advantage can be reverted to wild type levels using an inhibitor of MAP kinase kinase (Mek). The mESC of all NF1 types can also be differentiated into neuron-like cells. This novel model system provides an ideal paradigm for studies of the role of NF1 in cell growth and differentiation of the different cell types affected by NF1 in cells with differing levels of neurofibromin that are neither transformed nor malignant. (C) 2007 Wiley-Liss, Inc.