Conditional and domain-specific inactivation of the Tsc2 gene in neural progenitor cells.
Conditional and domain-specific inactivation of the Tsc2 gene in neural progenitor cells.
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DOI：
10.1002/dvg.22377
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发表时间：
2013-04
期刊：
影响因子：
1.5
通讯作者：
Ess, Kevin C.
中科院分区：
文献类型：
--
作者：
Fu, Cary;Ess, Kevin C.
结节性硬化症（TSC）是一种以多器官良性肿瘤和神经系统表现为特征的遗传性疾病。癫痫和自闭症是两种更常见的神经系统并发症，通常很严重。 TSC 是由 TSC1（编码错构蛋白）或 TSC2（编码马铃薯蛋白）基因突变引起的，TSC2 突变与更差的结果相关。马铃薯蛋白含有高度保守的 GTP 酶激活蛋白 (GAP) 结构域，可间接抑制哺乳动物雷帕霉素靶点复合物 1 (mTORC1)。目前认为 mTORC1 失调是 TSC 的大部分发病机制，但不依赖于 mTORC1 的机制也可能有所贡献。我们通过在外显子 36 和 37 两侧添加 loxP 位点，生成了 Tsc2 的新型条件等位基因。该敲入 Tsc2 等位基因纯合的小鼠可存活且具有生育能力，并具有正常的生长和发育。然后，暴露于 Cre 重组酶会产生涉及 GAP 结构域关键残基的框内删除。使用 Emx1Cre 生成的纯合条件突变小鼠皮质 mTORC1 信号传导增强、严重的大脑发育异常、癫痫发作并在三周内死亡。我们发现突变体 Tsc2 mRNA 的正常水平，但 GAP 缺陷的马铃薯蛋白似乎不稳定且快速降解。这种新颖的动物模型将允许进一步研究马铃薯块蛋白的功能，包括 GAP 结构域对蛋白质稳定性的要求。
Tuberous sclerosis complex (TSC) is a genetic disease characterized by multiorgan benign tumors as well as neurological manifestations. Epilepsy and autism are two of the more prevalent neurological complications and are usually severe. TSC is caused by mutations in either the TSC1 (encodes hamartin) or TSC2 (encodes tuberin) genes with TSC2 mutations being associated with worse outcomes. Tuberin contains a highly conserved GTPase activating protein (GAP) domain that indirectly inhibits mammalian target of rapamycin complex 1 (mTORC1). mTORC1 dysregulation is currently thought to cause much of the pathogenesis in TSC but mTORC1-independent mechanisms may also contribute. We generated a novel conditional allele of Tsc2 by flanking exons 36 and 37 with loxP sites. Mice homozygous for this knock-in Tsc2 allele are viable and fertile with normal appearing growth and development. Exposure to Cre recombinase then creates an in-frame deletion involving critical residues of the GAP domain. Homozygous conditional mutant mice generated using Emx1Cre have increased cortical mTORC1 signaling, severe developmental brain anomalies, seizures and die within three weeks. We found normal levels of the mutant Tsc2 mRNA though GAP-deficient tuberin protein appears unstable and rapidly degraded. This novel animal model will allow further study of tuberin function including the requirement of the GAP domain for protein stability.
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影响因子：
3.9
作者：
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通讯作者：
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发表时间：
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