K6irs1, K6irs2, K6irs3, and K6irs4 represent the inner-root-sheath-specific type II epithelial keratins of the human hair follicle.
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In this study we report on the cloning of two novel human type II keratin cDNAs, K6irs3 and K6irs4, which were specifically expressed in the inner root sheath of the hair follicle. Together with the genes of two previously described type II inner root sheath keratins, K6irs1 and K6irs2, the K6irs3 and K6irs4 genes were subclustered in the type II keratin/hair keratin gene domain on chromosome 12q13. Evolutionary tree analysis using all known type II epithelial and hair keratins revealed that the K6irs1-4 formed a branch separate from the other epithelial and hair keratins. RNA in situ hybridization and indirect immunofluorescence studies of human hair follicles, which also included the K6irs2 keratin, demonstrated that both K6irs2 and K6irs3 were specifically expressed in the inner root sheath cuticle, but showed a different onset of expression in this compartment. Whereas the K6irs3 expression began in the lowermost bulb region, that of K6irs2 was delayed up to the height of the apex of the dermal papilla. In contrast, the K6irs4 keratin was specifically expressed in the Huxley layer. Moreover, K6irs4 was ideally suited to further investigate the occurrence of Flugelzellen, i.e., Huxley cells, characterized by horizontal cell extensions that pass through the Henle layer, abut upon the companion layer, and form desmosomal connections with the surrounding cells. Previously, we detected Flugelzellen only in the region along the differentiated Henle layer. Using the Huxley-cell-specific K6irs4 antiserum, we now demonstrate this cell type to be clearly apposed to the entire Henle layer. We provide evidence that Flugelzellen penetrate the Henle layer actively and may play a role in conferring plasticity and resilience to the otherwise rigid upper Henle layer. (+info)
Dermal papilla-induced hair differentiation of adult epithelial stem cells from human skin.
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The epithelial-mesenchymal interactions between keratinocyte stem cells and dermal papilla (DP) cells are crucial for normal development of the hair follicle as well as during hair cycling. During the cyclical regrowth of a new lower follicle, the multipotent hair follicle stem cells are stimulated to proliferate and differentiate through interactions with the underlying mesenchymal DP cells. To characterize the events occurring during the process of epithelial stem cell fate determination, we utilized a coculture system by incubating human hair follicle keratinocyte stem cells with DP cells. Using GeneChip microarrays, we analyzed changes in gene expression within the stem cells upon coculture with the DP over a 5-day time course. A number of important signaling pathways and growth factors were regulated. The hair-specific keratin 6hf (K6hf) gene proved a particularly good marker of hair differentiation, with a 7.9-fold increase in mRNA and resulting increased protein levels. The high expression of K6hf was unique to DP-induced keratinocyte differentiation, since expression of K6hf was not induced by high calcium. Since the beta-catenin signaling pathway has been implicated in hair follicle development, we examined the role of beta-catenin in our system and demonstrated that beta-catenin/lef-1 signaling is required for DP-induced hair differentiation. (+info)
A mutation in the hair matrix and cuticle keratin KRTHB5 gene causes ectodermal dysplasia of hair and nail type.
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BACKGROUND: Ectodermal dysplasias are developmental disorders affecting tissues of ectodermal origin. To date, four different types of ectodermal dysplasia involving only hair and nails have been described. In an effort to understand the molecular bases of this form of ectodermal dysplasia, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. OBJECTIVE: To identify the gene underlying the phenotype. METHODS: Microsatellite markers were genotyped in candidate regions and two point and multipoint parametric linkage analysis carried out. RESULTS: The disease locus was mapped to a 16.6 centimorgan region on chromosome 12q12-q14.1 (Zmax = 8.2), which harbours six type II hair keratin genes. DNA sequence analysis revealed a homozygous missense mutation in the hair matrix and cuticle keratin KRTHB5, leading to histidine substitution of a conserved arginine residue (R78H) located in the head domain. CONCLUSIONS: This report provides the first direct evidence relating to the molecular pathogenesis of pure hair-nail ectodermal dysplasias. (+info)
K25 (K25irs1), K26 (K25irs2), K27 (K25irs3), and K28 (K25irs4) represent the type I inner root sheath keratins of the human hair follicle.
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The recent elucidation of the human type I keratin gene domain allowed the completion of the so far only partially characterized subcluster of type I keratin genes, KRT25-KRT28 (formerly KRT25A-KRT25D), representing the counterparts of the type II inner root sheath (IRS) keratin genes, KRT71-KRT74 (encoding proteins K71-K74, formerly K6irs1-K6irs4). Here, we describe the expression patterns of the type I IRS keratin proteins K25-K28 (formerly K25irs1-K25irs4) and their mRNAs. We found that K25 (K25irs1), K27 (K25irs3), and K28 (K25irs4) occur in the Henle layer, the Huxley layer, and in the IRS cuticle. Their expression extends from the bulb region up to the points of terminal differentiation of the three layers. In contrast, K26 (K25irs2) is restricted to the upper IRS cuticle. Apart from the three IRS layers, K25 (K25irs1), K27 (K25irs3), and K28 (K25irs4) are also present in the hair medulla. Based on previous, although controversial claims of the occurrence in the IRS of various "classical" epithelial keratins, we undertook a systematic study using antibodies against the presently described human epithelial and hair keratins and show that the type I keratins K25-K28 (K25irs1-K25irs4) and the type II keratins K71-K74 (K6irs1-K6irs4) represent the IRS keratins of the human hair follicle. (+info)
Mice expressing a mutant Krt75 (K6hf) allele develop hair and nail defects resembling pachyonychia congenita.
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KRT75 (formerly known as K6hf) is one of the isoforms of the keratin 6 (KRT6) family located within the type II cytokeratin gene cluster on chromosome 12 of humans and chromosome 15 of mice. KRT75 is expressed in the companion layer and upper germinative matrix region of the hair follicle, the medulla of the hair shaft, and in epithelia of the nail bed. Dominant mutations in members of the KRT6 family, such as in KRT6A and KRT6B cause pachyonychia congenita (PC) -1 and -2, respectively. To determine the function of KRT75 in skin appendages, we introduced a dominant mutation into a highly conserved residue in the helix initiation peptide of Krt75. Mice expressing this mutant form of Krt75 developed hair and nail defects resembling PC. This mouse model provides in vivo evidence for the critical roles played by Krt75 in maintaining hair shaft and nail integrity. Furthermore, the phenotypes observed in our mutant Krt75 mice suggest that KRT75 may be a candidate gene for screening PC patients who do not exhibit obvious mutations in KRT6A, KRT6B, KRT16, or KRT17, especially those with extensive hair involvement. (+info)
The keratins of the human beard hair medulla: the riddle in the middle.
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