A transgenic mouse model with an inducible skin blistering disease phenotype.
A transgenic mouse model with an inducible skin blistering disease phenotype.
复制标题
具有诱导性皮肤起泡疾病表型的转基因小鼠模型。
DOI：
10.1073/pnas.93.25.14776
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发表时间：
1996
影响因子：
11.1
通讯作者：
Coulombe,PA
中科院分区：
文献类型：
--
作者：
Takahashi,K;Coulombe,PA
目前涉及哺乳动物基因组的基因转移协议的局限性之一是缺乏对所需基因操作的空间和时间控制。从一个显示复杂调控的人角蛋白基因作为模板，我们确定了在成年转基因小鼠的复层上皮细胞亚群中可诱导基因表达的调控序列。我们使用这个盒式磁带制造了一种转基因小鼠，其皮肤起泡表型模仿了一种表皮松解性过度角化病，这是一种角蛋白基因紊乱。当局部应用佛波酯诱导时，突变的角蛋白转基因产物聚集在表皮的分化层，导致施加机械创伤后的角质形成细胞溶解。这一小鼠模型将有助于更好地理解角蛋白突变、角质形成细胞结构和创伤敏感性之间的复杂关系。具有良好细胞特异性的可诱导表达载体的开发，对于在转基因小鼠中以时空可控的方式操纵基因，以及利用皮肤作为组织源控制外源物质的基因治疗策略的设计具有重要意义。
One of the current limitations of gene transfer protocols involving mammalian genomes is the lack of spatial and temporal control over the desired gene manipulation. Starting from a human keratin gene showing a complex regulation as a template, we identified regulatory sequences that confer inducible gene expression in a subpopulation of keratinocytes in stratified epithelia of adult transgenic mice. We used this cassette to produce transgenic mice with an inducible skin blistering phenotype mimicking a form of epidermolytic hyperkeratosis, a keratin gene disorder. Upon induction by topical application of a phorbol ester, the mutant keratin transgene product accumulates in the differentiating layers of epidermis, leading to keratinocyte lysis after application of mechanical trauma. This mouse model will allow for a better understanding of the complex relationship between keratin mutation, keratinocyte cytoarchitecture, and hypersensitivity to trauma. The development of an inducible expression vector showing an exquisite cellular specificity has important implications for manipulating genes in a spatially and temporally controlled fashion in transgenic mice, and for the design of gene therapy strategies using skin as a tissue source for the controlled delivery of foreign substances.