Open AccessA transgenic mouse model with an inducible skin blistering disease phenotype
Author(s) -
Keiichi Takahashi,
Pierre A. Coulombe
Publication year - 1996
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.93.25.14776
Subject(s) - keratin 5 , transgene , keratin , keratin 14 , biology , keratin 6a , phenotype , epidermolysis bullosa simplex , epidermolytic hyperkeratosis , keratinocyte , microbiology and biotechnology , genetically modified mouse , gene , gene expression , transgenesis , epidermis (zoology) , genetics , cell , intermediate filament , cell culture , anatomy , cytoskeleton , reproductive biology , embryogenesis
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.