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

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 resp onse 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-n egative MK6a construct (Delta 2B-P) in the interfollicular epidermis caused severe blistering and neonatal lethality, suggesting that mutations in a y et to be identified basally expressed HK6 isoform might result in a severe blistering phenotype. Surviving Delta 2B-P animals showed transgene express ion only in isolated epidermal cells and not in all cells of the ORS, but n evertheless developed severe alopecia. Expression of two different C-termin al mutant transgenes also caused alopecia while a third C-terminal mutant h ad no phenotypic consequences. Electron microscopy revealed that Delta 2B-P expression resulted in the collapse of keratin filaments, while destructio n 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 sligh tly altered K6 proteins, suggesting that mutations affecting an HK6 isoform expressed in this cell layer could result in alopecia in humans as well.