Expression of MK6a dominant-negative and C-terminal mutant transgenes in mice has distinct phenotypic consequences in the epidermis and hair follicle

• Published in: Differentiation (London) Vol. 65; no. 2; pp. 97 - 112
• Main Authors: Wojcik, Sonja M., Imakado, Sumihisa, Seki, Toshihiko, Longley, Mary A., Petherbridge, Lee, Bundman, Donnie S., Bickenbach, Jackie R., Rothnagel, Joseph A., Roop, Dennis R.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Elsevier B.V 01.10.1999; Blackwell Publishing Ltd; Blackwell
• Subjects: Age of Onset; Alopecia - genetics; Amino Acid Sequence; Animals; Animals, Newborn; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Epidermis - metabolism; Epidermis - pathology; Epidermis - ultrastructure; Fundamental and applied biological sciences. Psychology; Gene Expression; Genes, Dominant; Hair Follicle - metabolism; Hair Follicle - pathology; Hair Follicle - ultrastructure; Keratins - biosynthesis; Keratins - genetics; Keratins - ultrastructure; Mice; Mice, Inbred BALB C; Mice, Transgenic; Microscopy, Electron; Molecular and cellular biology; Molecular Sequence Data; Mutagenesis, Site-Directed; Phenotype; Protein Isoforms - biosynthesis; Protein Isoforms - genetics; Skin Diseases - genetics; Skin Diseases - pathology; Time Factors; Transgenes; Hair; Animal model; Skin disease; Rodentia; Transgenic animal; Epidermis; Hair follicle; Cell differentiation; Gene expression; Keratin; Vertebrata; Phenotype; Mammalia; Alopecia; Mouse; Mutation
• ISSN: 0301-4681; 1432-0436
• DOI: 10.1046/j.1432-0436.1999.6520097.x

Mouse keratin 6a (MK6a) is constitutively expressed in a single cell layer of the outer root sheath (ORS) of hair follicles, but its synthesis can be induced in interfollicular epidermis including the basal cell layer in response to perturbing stimuli. A basally inducible human K6 (HK6) isoform has not been described, and it is not clear which of the known HK6 isoforms is expressed in the ORS. In this study we show that expression of a dominant-negative MK6a construct (Δ2B-P) in the interfollicular epidermis caused severe blistering and neonatal lethality, suggesting that mutations in a yet to be identified basally expressed HK6 isoform might result in a severe blistering phenotype. Surviving Δ2B-P animals showed transgene expression only in isolated epidermal cells and not in all cells of the ORS, but nevertheless developed severe alopecia. Expression of two different C-terminal mutant transgenes also caused alopecia while a third C-terminal mutant had no phenotypic conse- quences. Electron microscopy revealed that Δ2B-P expression resulted in the collapse of keratin filaments, while destruction of hair follicles in the two phenotypic C-terminal mutant lines occurred in the absence of filament abnormalities. The latter finding indicates that the innermost ORS cells are uniquely sensitive to expression of even slightly altered K6 proteins, suggesting that mutations affecting an HK6 isoform expressed in this cell layer could result in alopecia in humans as well.