Strain background influences neurotoxicity and behavioral abnormalities in mice expressing the tetracycline transactivator.
Strain background influences neurotoxicity and behavioral abnormalities in mice expressing the tetracycline transactivator.
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菌株背景影响表达四环素反式激活蛋白的小鼠的神经毒性和行为异常。
DOI：
10.1523/jneurosci.0893-12.2012
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发表时间：
2012-08-01
期刊：
影响因子：
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通讯作者：
Jankowsky JL
中科院分区：
文献类型：
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作者：
Han HJ;Allen CC;Buchovecky CM;Yetman MJ;Born HA;Marin MA;Rodgers SP;Song BJ;Lu HC;Justice MJ;Probst FJ;Jankowsky JL
tet-off系统已被广泛用于创建神经系统疾病的转基因模型，包括阿尔茨海默氏症、帕金森氏症、亨廷顿氏症和朊病毒病。该系统的实用性在于假设四环素反式激活因子（TTA）作为一种惰性控制元件，并没有在研究中的表型作出贡献。在这里，我们报告说，神经元表达TTA可以影响海马细胞结构和行为的应变依赖性方式。在研究两个tet-off阿尔茨海默病模型中的神经变性时，我们意外地发现了单个转基因TTA对照的齿状回内的神经元损失。颗粒神经元出现TTA暴露在出生后的发展，在此期间的多西环素治疗是神经保护。TTA诱导的变性可以通过将转基因转移到同源C57 BL/6 J背景上来挽救，并且在重新引入CBA或C3 H/He背景时复发。B6 C3 F2 TTA小鼠的数量性状分析确定了14号染色体上的一个区域，该区域包含神经退行性表型的主要修饰物。虽然B6小鼠对退化有抵抗力，但它们并不适合进行认知测试。TTA C57 BL/6 J和129 X1/SvJ，FVB/NJ或DBA/1 J的F1后代表现出改善的空间学习能力，但TTA表达在这些背景中的两个背景上引起了背景恐惧条件反射的细微差异，表明菌株和基因型在不同的行为环境下可以独立地相互作用。所有的模型系统都有局限性，应认识到并减轻在可能的情况下，我们的研究结果强调映射TTA单独与tet关闭模型时所造成的影响的重要性。
The tet-off system has been widely used to create transgenic models of neurological disorders including Alzheimer’s, Parkinson’s, Huntington’s, and prion disease. The utility of this system lies in the assumption that the tetracycline transactivator (TTA) acts as an inert control element and does not contribute to phenotypes under study. Here we report that neuronal expression of TTA can affect hippocampal cytoarchitecture and behavior in a strain-dependent manner. While studying neurodegeneration in two tet-off Alzheimer’s disease models, we unexpectedly discovered neuronal loss within the dentate gyrus of single transgenic TTA controls. Granule neurons appeared most sensitive to TTA exposure during postnatal development, and doxycycline treatment during this period was neuroprotective. TTA-induced degeneration could be rescued by moving the transgene onto a congenic C57BL/6J background, and recurred on re-introduction of either CBA or C3H/He backgrounds. Quantitative trait analysis of B6C3 F2 TTA mice identified a region on Chromosome 14 that contains a major modifier of the neurodegenerative phenotype. Although B6 mice were resistant to degeneration, they were not ideal for cognitive testing. F1 offspring of TTA C57BL/6J and 129X1/SvJ, FVB/NJ, or DBA/1J showed improved spatial learning, but TTA expression caused subtle differences in contextual fear conditioning on two of these backgrounds indicating that strain and genotype can interact independently under different behavioral settings. All model systems have limitations that should be recognized and mitigated where possible; our findings stress the importance of mapping the effects caused by TTA alone when working with tet-off models.