A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy.
A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy.
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DOI：
10.1371/journal.pone.0192657
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Jones PL
中科院分区：
文献类型：
--
作者：
Jones T;Jones PL
双同源框 4 (DUX4) 基因是人类早期发育的重要调节因子，其异常表达是面肩肱型肌营养不良症 (FSHD) 的原因。 DUX4 全长 (DUX4-fl) mRNA 剪接异构体编码转录激活因子；然而，DUX4 及其独特的 DNA 结合偏好是旧世界灵长类动物所特有的。无论如何，DUX4 表达引起的体细胞毒性在细胞和动物（从果蝇到小鼠）中表达时是保守的。因此，基于 DUX4-fl 表达的可行动物模型很难产生，这在很大程度上是由于渗漏转基因的低 DUX4-fl 表达的明显发育毒性。我们已经克服了这一障碍，在这里我们报告了一系列条件性 floxed DUX4-fl 转基因小鼠 FLExDUX4 的产生和初步表征，该小鼠系具有活力且可繁殖。在缺乏 cre 的情况下，这些小鼠从转基因中表达非常低水平的 DUX4-fl mRNA，从而导致轻微的表型。然而，当与适当的cre驱动小鼠系杂交时，双转基因后代很容易表达DUX4-fl mRNA、蛋白质和靶基因，其核cre表达的时空模式由所选系统决定。当cre从ACTA1骨骼肌特异性启动子表达时，双转基因动物表现出发育性肌病。当与他莫昔芬诱导的 cre 系杂交时，可以在成年动物中诱导 DUX4 介导的病理学。因此，可以控制病理学的出现和进展以提供可用于评估靶向DUX4-f1 mRNA和蛋白质的治疗方法的易于筛选的表型。总体而言，FLExDUX4 小鼠系非常通用，将允许对 DUX4 介导的病理生理学机制进行新的研究，并对 DUX4 靶向 FSHD 干预措施进行体内急需的临床前测试。
The Double homeobox 4 (DUX4) gene is an important regulator of early human development and its aberrant expression is causal for facioscapulohumeral muscular dystrophy (FSHD). The DUX4-full length (DUX4-fl) mRNA splice isoform encodes a transcriptional activator; however, DUX4 and its unique DNA binding preferences are specific to old-world primates. Regardless, the somatic cytotoxicity caused by DUX4 expression is conserved when expressed in cells and animals ranging from fly to mouse. Thus, viable animal models based on DUX4-fl expression have been difficult to generate due in large part to overt developmental toxicity of low DUX4-fl expression from leaky transgenes. We have overcome this obstacle and here we report the generation and initial characterization of a line of conditional floxed DUX4-fl transgenic mice, FLExDUX4, that is viable and fertile. In the absence of cre, these mice express a very low level of DUX4-fl mRNA from the transgene, resulting in mild phenotypes. However, when crossed with appropriate cre-driver lines of mice, the double transgenic offspring readily express DUX4-fl mRNA, protein, and target genes with the spatiotemporal pattern of nuclear cre expression dictated by the chosen system. When cre is expressed from the ACTA1 skeletal muscle-specific promoter, the double transgenic animals exhibit a developmental myopathy. When crossed with tamoxifen-inducible cre lines, DUX4-mediated pathology can be induced in adult animals. Thus, the appearance and progression of pathology can be controlled to provide readily screenable phenotypes useful for assessing therapeutic approaches targeting DUX4-fl mRNA and protein. Overall, the FLExDUX4 line of mice is quite versatile and will allow new investigations into mechanisms of DUX4-mediated pathophysiology as well as much-needed pre-clinical testing of DUX4-targeted FSHD interventions in vivo.
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DOI：
10.1006/bbrc.1997.7124
发表时间：
1997-08-28
影响因子：
3.1
作者：
Feil, R;Wagner, J;Chambon, P
通讯作者：
Chambon, P
影响因子：
2.2
作者：
Harrell, Maria I.;Iritani, Brian M.;Ruddell, Alanna
通讯作者：
Ruddell, Alanna
影响因子：
2.6
作者：
Hayashi, Shigemi;Lewis, Paula;McMahon, Andrew P.
通讯作者：
McMahon, Andrew P.
影响因子：
64.5
作者：
JEGALIAN, BG;DEROBERTIS, EM
通讯作者：
DEROBERTIS, EM
影响因子：
3.7
作者：
Chen CM;Krohn J;Bhattacharya S;Davies B
通讯作者：
Davies B