Increased expression of keratin 16 causes anomalies in cytoarchitecture and keratinization in transgenic mouse skin.
Injury to epidermis and other stratified epithelia triggers profound but transient changes in the pattern of keratin expression. In postmitotic cells located at the wound edge, a strong induction of K6, K16, and K17 synthesis occurs at the expense of the keratins produced under the normal situation. The functional significance of these alterations in keratin expression is not known. Here, we report that overexpression of a wild-type human K16 gene in a tissue-specific fashion in transgenic mice causes aberrant keratinization of the hair follicle outer root sheath and proximal epidermis, and it leads to hyperproliferation and increased thickness of the living layers (acanthosis), as well as cornified layers (hyperkeratosis). The pathogenesis of lesions in transgenic mouse skin begins with a reorganization of keratin filaments in postmitotic keratinocytes, and it progresses in a transgene level-dependent fashion to include disruption of keratinocyte cytoarchitecture and structural alterations in desmosomes at the cell surface. No evidence of cell lysis could be found at the ultrastructural level. These results demonstrate that the disruption of the normal keratin profile caused by increased K16 expression interferes with the program of terminal differentiation in outer root sheath and epidermis. They further suggest that when present at sufficiently high intracellular levels, K16, along with K6 and K17, appear capable of inducing a reorganization of keratin filaments in the cytoplasm of skin epithelial cells.
Takahashi
K
K
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Folmer
J
J
Coulombe
P A
PA
D000051:Acantholysis / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion; D003599:Cytoskeleton / Q000648:ultrastructure; D003896:Desmosomes / Q000648:ultrastructure; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006197:Hair / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000473:pathology*; D007633:Keratins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D010641:Phenotype; D012871:Skin Diseases / Q000209:etiology / Q000473:pathology*
D007633:Keratins