Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas
Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas
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DOI：
10.1093/emboj/16.10.2621
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发表时间：
1997-05-15
期刊：
影响因子：
11.4
通讯作者：
Wakefield, LM
中科院分区：
文献类型：
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作者：
Bottinger, EP;Jakubczak, JL;Wakefield, LM
在转基因小鼠中使用显性阴性突变受体（DNR）方法，我们在功能上灭活了转化生长因子β显性负突变II型TGF-β受体阻断转基因小鼠产生的原代肝细胞和胰腺腺泡细胞培养物中所有三种TGF-β同种型的信号传导，如生长抑制和基因诱导应答的丧失所证实的，然而，它对激活素（最接近的TGF-β家族成员）的信号传导没有影响，DNR转基因小鼠显示胰腺腺泡细胞增殖增加和腺泡分化严重紊乱。这些结果表明，TGF-β负性控制腺泡细胞的生长，并且对于维持体外胰腺中分化的腺泡表型是必需的。相反，在肝脏中没有观察到这种异常。胰腺中的其他异常包括纤维化、新血管生成和轻度巨噬细胞浸润，并且这些与转基因腺泡细胞中TGF-β表达的显著上调有关。TGF-β信号传导的靶向功能失活的这种转基因模型提供了对TGF-β反应性丧失可能促进致癌过程的机制的见解，通过对细胞增殖的直接作用和通过TGF-β的上调以及对间质区室的相关旁分泌作用间接作用。
Using a dominant-negative mutant receptor (DNR) approach in transgenic mice, we have functionally inactivated transforming growth factor-beta (TGF-beta) signaling in select epithelial cells, The dominant-negative mutant type II TGF-beta receptor blocked signaling by all three TGF-beta isoforms in primary hepatocyte and pancreatic acinar cell cultures generated from transgenic mice, as demonstrated by the loss of growth inhibitory and gene induction responses, However, it had no effect on signaling by activin, the closest TGF-beta family member, DNR transgenic mice showed increased proliferation of pancreatic acinar cells and severely perturbed acinar differentiation. These results indicate that TGF-beta negatively controls growth of acinar cells and is essential for the maintenance of a differentiated acinar phenotype in the exocrine pancreas in vivo. In contrast, such abnormalities were not observed in the liver, Additional abnormalities in the pancreas included fibrosis, neoangiogenesis and mild macrophage infiltration, and these were associated with a marked up-regulation of TGF-beta expression in transgenic acinar cells, This transgenic model of targeted functional inactivation of TGF-beta signaling provides insights into mechanisms whereby loss of TGF-beta responsiveness might promote the carcinogenic process, both through direct effects on cell proliferation, and indirectly through up-regulation of TGF-beta s with associated paracrine effects on stromal compartments.