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THE KERATINS OF THE HUMAN HAIR FOLLICLE Hair is the differentiation product of a special type of epithelial cells, called trichocytes, which occupy the innermost, hair-forming compartment of the hair follicle. This compartment comprises the germinative matrix, which differentiates into the hair cortex and eventually, a central medulla. Both the hair matrix and cortex are surrounded by the hair cuticle, which represents the external coat of the hair. Adjacent to the hair cuticle is the inner root sheath, IRS, which consists of three independent tissue layers, the IRS cuticle, the Huxley layer and the Henle layer, the latter being apposed to the companion layer. The most external layer of the hair follicle is the outer root sheath, ORS. In the past decade, we have focused on the biology and genetics of the major classes of structural proteins of the hair follicle which comprise the hair keratins and their associated proteins, KAPs as constituents of the hair-forming compartment, as well as epithelial keratins involved in the formation of the IRS and the companion layer of the follicle. While older studies suggested the existence of only 10 hair keratins, we now know, that there are 17 functional hair keratin genes, 11 type I and 6 type II, which are each clustered within the large type I and type II epithelial keratin gene domains on chromosomes 17q21.2 and 12q13.13, respectively. On both domains, groups of hair keratin genes form subclusters of structurally related or heterogeneous members, this grouping being reflected by the expression properties of the encoded keratins in the hair forming compartment. There is strong evidence that the complex differential expression of human hair keratins involves the transcription factors HOXC13, LEF1/ß-catenin, Foxn1 and the androgen receptor, AR. Comparisons of human hair keratin genes with those of our closest primate relatives shed light on the evolution of anatomically modern humans. Similar to mutated epidermal keratins, mutated hair keratins should be causal for hereditary hair disorders. Among these, we identified monilethrix as a disease of the hair cortex, as deleterious mutations were restricted to type II cortex keratins. A still unsolved problem is the absence of disease-causing mutations in type I cortex keratins. Investigations in a multitude of hair follicle derived tumors revealed pilomatricomas as the only tumors expressing hair keratins. Considering that the ORS is a continuation of the interfollicular epidermis, conceptually, hair follicle-specific epithelial keratins should only occur in the IRS and the companion layer. Indeed, we were able to identify eight novel epithelial keratins, which are differentially expressed in the IRS. By means of a Huxley layer-specific keratin, we rediscovered so called "Flügelzellen" i.e. Huxley cells tightly connected by desmosomes to the companion layer through cell processes which actively traverse the Henle layer along its entire length. The companion layer/Flügelzell connection involves another hair follicle-specific keratin, K6hf, in companion layer cells. Keratin K6hf is, however, also expressed in the hair medulla, which represents the only tissue compartment of the hair follicle exhibiting co-expression of hair and epithelial keratins. Up to now, hereditary hair disorders caused by IRS keratins have only been described in mice, while mutated K6hf seems to be a risk factor for the common hair disorder pseudofolliculitis barbae. The availability of antibodies against hair follicle-specific keratins enabled us to analyze cell fate determination and specific tissue differentiation of transiently dividing cells in the germinative matrix, which are constantly supplied by stem cells migrating from the bulge through the ORS. Last but not least, our detailed analysis of keratin expression in the various tissue compartments of the hair follicle made it possible to define each of them at the molecular level by means of a specific keratin.
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