An Inducible Mouse Model for Epidermolysis Bullosa Simplex: Implications for Gene Therapy

• Published in: The Journal of cell biology 2001-02, Vol.152 (3), p.651-656
• Main Authors: Cao, Tongyu, Longley, Mary Ann, Wang, Xiao-Jing, Roop, Dennis R.
• Format: Article
• Language: English
• Subjects: Animals; Blisters; Blotting, Southern; Cells; Cellular biology; Disease Models, Animal; DNA; Epidermolysis bullosa; Epidermolysis Bullosa Simplex - genetics; Epidermolysis Bullosa Simplex - pathology; Epidermolysis Bullosa Simplex - physiopathology; Epidermolysis Bullosa Simplex - therapy; Gene Expression Regulation; Gene therapy; Genetic mutation; Genetic Therapy; Humans; Integrases - genetics; Integrases - metabolism; Keratin-14; Keratins; Keratins - genetics; Keratins - metabolism; Luteolytic Agents - pharmacology; Mice; Mice, Transgenic; Microscopy, Fluorescence; Mifepristone - administration & dosage; Mifepristone - pharmacology; Phenotypes; Pups; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Skin; Skin - drug effects; Skin - physiopathology; Skin - ultrastructure; Stem cells; Viral Proteins
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.152.3.651

The Dowling-Meara variant of epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease inherited in an autosomal-dominant fashion. Here we report the generation of a mouse model that allows focal activation of a mutant keratin 14 allele in epidermal stem cells upon topical administration of an inducer, resulting in EBS phenotypes in treated areas. Using laser capture microdissection, we show that induced blisters healed by migration of surrounding nonphenotypic stem cells into the wound bed. This observation provides an explanation for the lack of mosaic forms of EBS-DM. In addition, we show that decreased mutant keratin 14 expression resulted in normal morphology and functions of the skin. Our results have important implications for gene therapy of EBS and other dominantly inherited diseases.