Transgenic expression of the N525S-tuberin variant in Tsc2 mutant (Eker) rats causes dominant embryonic lethality.
Transgenic expression of the N525S-tuberin variant in Tsc2 mutant (Eker) rats causes dominant embryonic lethality.
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DOI：
10.1038/srep05927
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发表时间：
2014-08-04
影响因子：
4.6
通讯作者：
Hino O
中科院分区：
文献类型：
--
作者：
Shiono M;Kobayashi T;Takahashi R;Ueda M;Ishioka C;Hino O
Tsc 2产物，tuberin，负调节mTOR途径。我们利用Eker（Tsc 2突变）大鼠系统来分析各种Tsc 2突变。在这里，我们专注于N525 S-Tsc 2变异体（NSM），即使观察到mTOR的正常抑制，该变异体也会引起患者的明显症状。出乎意料的是，我们多次无法产生携带NSM转基因的存活大鼠。基因型分析显示，大多数携带转基因的胚胎在胚胎发育14.5天后死亡，这与Eker纯合子的致死阶段相似。因此，NSM转基因似乎在我们的大鼠模型中具有显性致死效应。此外，与WT相比，在瞬时表达的NSM细胞中未观察到各种信号转导分子的显著差异。这些结果表明，一个非mTOR途径，胚胎发生的关键，是由块茎蛋白调节，提供了一个联系之间的块茎蛋白表达和Tsc 2突变相关的发病机制的严重性。
The Tsc2 product, tuberin, negatively regulates the mTOR pathway. We have exploited the Eker (Tsc2-mutant) rat system to analyse various Tsc2 mutations. Here, we focus on the N525S-Tsc2 variant (NSM), which is known to cause distinct symptoms in patients even though normal suppression of mTOR is observed. Unexpectedly, we were repeatedly unable to generate viable rats carrying the NSM transgene. Genotypic analysis revealed that most of the embryos carrying the transgene died around embryonic day after 14.5—similar to the stage of lethality observed for Eker homozygotes. Thus, the NSM transgene appeared to have a dominant lethal effect in our rat model. Further, no significant differences were observed for various signal transduction molecules in transiently expressed NSM cells compared to WT. These results indicate that a non-mTOR pathway, critical for embryogenesis, is being regulated by tuberin, providing a link between tuberin expression and the severity of Tsc2 mutation-related pathogenesis.