Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice
Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice
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DOI：
10.1038/sj.onc.1206230
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发表时间：
2003-04-03
期刊：
影响因子：
8
通讯作者：
Carbone, DP
中科院分区：
文献类型：
--
作者：
Dang, TP;Eichenberger, S;Carbone, DP
Notch3是一种跨膜受体，是Notch信号通路的成员，对无脊椎动物和脊椎动物多种发育组织中的细胞分化至关重要。新出现的数据支持Notch信号通路在肿瘤发生中的作用。我们先前已经证明了Notch3在一部分肺腺癌中的表达。为了进一步阐明Notch3在肺癌发展中的作用，我们建立了一个转基因小鼠模型，利用表面活性蛋白C启动子/增强子来表达Notch3的胞内结构域。在发育中的肺外周上皮中Notch3的组成性表达导致肺形态改变和发育延迟，导致这些转基因小鼠在围产期死亡。细胞特异性标记物和电子显微镜检查显示，大多数上皮细胞未分化，伴有一些Ⅱ型肺细胞的成熟。没有明显的Ⅰ型肺泡细胞。还观察到终末气道中未分化细胞的化生。尽管这些小鼠存活时间不足以评估肿瘤的发展，但这些发现表明，Notch3在气道上皮中的异位表达可能通过抑制终末分化促进肺癌的多步骤演变。
Notch3 is a transmembrane receptor and a member of the Notch signaling pathway essential for cellular differentiation in a variety of developing tissues in both invertebrates and vertebrates. Emerging data support the role of the Notch signaling pathway in tumorigenesis. We have previously demonstrated the expression of Notch3 in a subset of lung adenocarcinomas. To further elucidate the role of Notch3 in development of lung cancer, we established a transgenic mouse model in which the intracellular domain of Notch3 is expressed using the surfactant protein C promoter/enhancer. Constitutive expression of Notch3 in the peripheral epithelium in the developing lung resulted in altered lung morphology and delayed development, leading to perinatal lethality in these transgenic mice. Cell-specific markers and electron microscopy examination showed that the majority of the epithelial cells are undifferentiated, with some maturation of type 11 pneumocytes. No type I alveolar cells were evident. Metaplasia of undifferentiated cells in the terminal airways was also observed. Although the mice did not live long enough to assess tumor development, these findings demonstrate that ectopic expression of Notch3 in airway epithelium potentially contributes to the multistep evolution of lung cancer through the inhibition of terminal differentiation.