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. 1989 Nov 1;109(5):2295–2312. doi: 10.1083/jcb.109.5.2295

Expression of keratin K14 in the epidermis and hair follicle: insights into complex programs of differentiation

PMCID: PMC2115845  PMID: 2478566

Abstract

Keratins K14 and K5 have long been considered to be biochemical markers of the stratified squamous epithelia, including epidermis (Moll, R., W. Franke, D. Schiller, B. Geiger, and R. Krepler. 1982. Cell. 31:11-24; Nelson, W., and T.-T. Sun. 1983. J. Cell Biol. 97:244-251). When cells of most stratified squamous epithelia differentiate, they downregulate expression of mRNAs encoding these two keratins and induce expression of new sets of keratins specific for individual programs of epithelial differentiation. Frequently, as in the case of epidermis, the expression of differentiation-specific keratins also leads to a reorganization of the keratin filament network, including denser bundling of the keratin fibers. We report here the use of monospecific antisera and cRNA probes to examine the differential expression of keratin K14 in the complex tissue of human skin. Using in situ hybridizations and immunoelectron microscopy, we find that the patterns of K14 expression and filament organization in the hair follicle are strikingly different from epidermis. Some of the mitotically active outer root sheath (ORS) cells, which give rise to ORS under normal circumstances and to epidermis during wound healing, produce only low levels of K14. These cells have fewer keratin filaments than basal epidermal cells, and the filaments are organized into looser, more delicate bundles than is typical for epidermis. As these cells differentiate, they elevate their expression of K14 and produce denser bundles of keratin filaments more typical of epidermis. In contrast to basal cells of epidermis and ORS, matrix cells, which are relatively undifferentiated and which can give rise to inner root sheath, cuticle and hair shaft, show no evidence of K14, K14 mRNA expression, or keratin filament formation. As matrix cells differentiate, they produce hair-specific keratins and dense bundles of keratin filaments but they do not induce K14 expression. Collectively, the patterns of K14 and K14 mRNA expression and filament organization in mitotically active epithelial cells of the skin correlate with their relative degree of pluripotency, and this suggests a possible basis for the deviation of hair follicle programs of differentiation from those of other stratified squamous epithelia.

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Selected References

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  1. Albers K., Fuchs E. Expression of mutant keratin cDNAs in epithelial cells reveals possible mechanisms for initiation and assembly of intermediate filaments. J Cell Biol. 1989 Apr;108(4):1477–1493. doi: 10.1083/jcb.108.4.1477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Albers K., Fuchs E. The expression of mutant epidermal keratin cDNAs transfected in simple epithelial and squamous cell carcinoma lines. J Cell Biol. 1987 Aug;105(2):791–806. doi: 10.1083/jcb.105.2.791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. BIRBECK M. S., MERCER E. H. The electron microscopy of the human hair follicle. I. Introduction and the hair cortex. J Biophys Biochem Cytol. 1957 Mar 25;3(2):203–214. doi: 10.1083/jcb.3.2.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bártek J., Bártková J., Taylor-Papadimitriou J., Rejthar A., Kovarík J., Lukás Z., Vojtesek B. Differential expression of keratin 19 in normal human epithelial tissues revealed by monospecific monoclonal antibodies. Histochem J. 1986 Oct;18(10):565–575. doi: 10.1007/BF01675198. [DOI] [PubMed] [Google Scholar]
  5. Chapman R. E., Downes A. M., Wilson P. A. Migration and keratinization of cells in wool follicles. Aust J Biol Sci. 1980 Oct;33(5):587–603. doi: 10.1071/bi9800587. [DOI] [PubMed] [Google Scholar]
  6. Clausen O. P., Thorud E., Elgjo K. Epidermal proliferation characteristics are similar in the pilary canal of mouse hair follicles and in interfollicular epidermis. Virchows Arch B Cell Pathol Incl Mol Pathol. 1982;39(3):259–266. doi: 10.1007/BF02892852. [DOI] [PubMed] [Google Scholar]
  7. Cox K. H., DeLeon D. V., Angerer L. M., Angerer R. C. Detection of mrnas in sea urchin embryos by in situ hybridization using asymmetric RNA probes. Dev Biol. 1984 Feb;101(2):485–502. doi: 10.1016/0012-1606(84)90162-3. [DOI] [PubMed] [Google Scholar]
  8. Demarchez M., Sengel P., Prunieras M. Wound healing of human skin transplanted onto the nude mouse. I. An immunohistological study of the reepithelialization process. Dev Biol. 1986 Jan;113(1):90–96. doi: 10.1016/0012-1606(86)90110-7. [DOI] [PubMed] [Google Scholar]
  9. Eichner R., Bonitz P., Sun T. T. Classification of epidermal keratins according to their immunoreactivity, isoelectric point, and mode of expression. J Cell Biol. 1984 Apr;98(4):1388–1396. doi: 10.1083/jcb.98.4.1388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Eichner R., Sun T. T., Aebi U. The role of keratin subfamilies and keratin pairs in the formation of human epidermal intermediate filaments. J Cell Biol. 1986 May;102(5):1767–1777. doi: 10.1083/jcb.102.5.1767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. French P. W., Hewish D. R. Localization of low-sulfur keratin proteins in the wool follicle using monoclonal antibodies. J Cell Biol. 1986 Apr;102(4):1412–1418. doi: 10.1083/jcb.102.4.1412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fuchs E. V., Coppock S. M., Green H., Cleveland D. W. Two distinct classes of keratin genes and their evolutionary significance. Cell. 1981 Nov;27(1 Pt 2):75–84. doi: 10.1016/0092-8674(81)90362-7. [DOI] [PubMed] [Google Scholar]
  13. Fuchs E., Green H. Changes in keratin gene expression during terminal differentiation of the keratinocyte. Cell. 1980 Apr;19(4):1033–1042. doi: 10.1016/0092-8674(80)90094-x. [DOI] [PubMed] [Google Scholar]
  14. Fuchs E., Marchuk D. Type I and type II keratins have evolved from lower eukaryotes to form the epidermal intermediate filaments in mammalian skin. Proc Natl Acad Sci U S A. 1983 Oct;80(19):5857–5861. doi: 10.1073/pnas.80.19.5857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fuchs E., Tyner A. L., Giudice G. J., Marchuk D., RayChaudhury A., Rosenberg M. The human keratin genes and their differential expression. Curr Top Dev Biol. 1987;22:5–34. doi: 10.1016/s0070-2153(08)60097-6. [DOI] [PubMed] [Google Scholar]
  16. Hanukoglu I., Fuchs E. The cDNA sequence of a human epidermal keratin: divergence of sequence but conservation of structure among intermediate filament proteins. Cell. 1982 Nov;31(1):243–252. doi: 10.1016/0092-8674(82)90424-x. [DOI] [PubMed] [Google Scholar]
  17. Hashimoto K. The ultrastructure of the skin of human embryos. IX. Formation of the hair cone and intraepidermal hair canal. Arch Klin Exp Dermatol. 1970;238(4):333–345. doi: 10.1007/BF00525727. [DOI] [PubMed] [Google Scholar]
  18. Heid H. W., Moll I., Franke W. W. Patterns of expression of trichocytic and epithelial cytokeratins in mammalian tissues. I. Human and bovine hair follicles. Differentiation. 1988;37(2):137–157. doi: 10.1111/j.1432-0436.1988.tb00805.x. [DOI] [PubMed] [Google Scholar]
  19. Heid H. W., Moll I., Franke W. W. Patterns of expression of trichocytic and epithelial cytokeratins in mammalian tissues. II. Concomitant and mutually exclusive synthesis of trichocytic and epithelial cytokeratins in diverse human and bovine tissues (hair follicle, nail bed and matrix, lingual papilla, thymic reticulum). Differentiation. 1988 May;37(3):215–230. doi: 10.1111/j.1432-0436.1988.tb00724.x. [DOI] [PubMed] [Google Scholar]
  20. Heid H. W., Werner E., Franke W. W. The complement of native alpha-keratin polypeptides of hair-forming cells: a subset of eight polypeptides that differ from epithelial cytokeratins. Differentiation. 1986;32(2):101–119. doi: 10.1111/j.1432-0436.1986.tb00562.x. [DOI] [PubMed] [Google Scholar]
  21. Ito M., Tazawa T., Shimizu N., Ito K., Katsuumi K., Sato Y., Hashimoto K. Cell differentiation in human anagen hair and hair follicles studied with anti-hair keratin monoclonal antibodies. J Invest Dermatol. 1986 May;86(5):563–569. doi: 10.1111/1523-1747.ep12355183. [DOI] [PubMed] [Google Scholar]
  22. Ito M. The innermost cell layer of the outer root sheath in anagen hair follicle: light and electron microscopic study. Arch Dermatol Res. 1986;279(2):112–119. doi: 10.1007/BF00417531. [DOI] [PubMed] [Google Scholar]
  23. Kim K. H., Schwartz F., Fuchs E. Differences in keratin synthesis between normal epithelial cells and squamous cell carcinomas are mediated by vitamin A. Proc Natl Acad Sci U S A. 1984 Jul;81(14):4280–4284. doi: 10.1073/pnas.81.14.4280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kopan R., Fuchs E. A new look into an old problem: keratins as tools to investigate determination, morphogenesis, and differentiation in skin. Genes Dev. 1989 Jan;3(1):1–15. doi: 10.1101/gad.3.1.1. [DOI] [PubMed] [Google Scholar]
  25. Kopan R., Traska G., Fuchs E. Retinoids as important regulators of terminal differentiation: examining keratin expression in individual epidermal cells at various stages of keratinization. J Cell Biol. 1987 Jul;105(1):427–440. doi: 10.1083/jcb.105.1.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lane E. B., Bártek J., Purkis P. E., Leigh I. M. Keratin antigens in differentiating skin. Ann N Y Acad Sci. 1985;455:241–258. doi: 10.1111/j.1749-6632.1985.tb50415.x. [DOI] [PubMed] [Google Scholar]
  27. Lawrence J. B., Singer R. H. Intracellular localization of messenger RNAs for cytoskeletal proteins. Cell. 1986 May 9;45(3):407–415. doi: 10.1016/0092-8674(86)90326-0. [DOI] [PubMed] [Google Scholar]
  28. Lynch M. H., O'Guin W. M., Hardy C., Mak L., Sun T. T. Acidic and basic hair/nail ("hard") keratins: their colocalization in upper cortical and cuticle cells of the human hair follicle and their relationship to "soft" keratins. J Cell Biol. 1986 Dec;103(6 Pt 2):2593–2606. doi: 10.1083/jcb.103.6.2593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mansbridge J. N., Knapp A. M. Changes in keratinocyte maturation during wound healing. J Invest Dermatol. 1987 Sep;89(3):253–263. doi: 10.1111/1523-1747.ep12471216. [DOI] [PubMed] [Google Scholar]
  30. Marchuk D., McCrohon S., Fuchs E. Remarkable conservation of structure among intermediate filament genes. Cell. 1984 Dec;39(3 Pt 2):491–498. doi: 10.1016/0092-8674(84)90456-2. [DOI] [PubMed] [Google Scholar]
  31. Moll I., Heid H. W., Franke W. W., Moll R. Patterns of expression of trichocytic and epithelial cytokeratins in mammalian tissues. III. Hair and nail formation during human fetal development. Differentiation. 1988 Dec;39(3):167–184. doi: 10.1111/j.1432-0436.1988.tb00092.x. [DOI] [PubMed] [Google Scholar]
  32. Moll R., Franke W. W., Schiller D. L., Geiger B., Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982 Nov;31(1):11–24. doi: 10.1016/0092-8674(82)90400-7. [DOI] [PubMed] [Google Scholar]
  33. Moll R., Moll I., Wiest W. Changes in the pattern of cytokeratin polypeptides in epidermis and hair follicles during skin development in human fetuses. Differentiation. 1982;23(2):170–178. doi: 10.1111/j.1432-0436.1982.tb01280.x. [DOI] [PubMed] [Google Scholar]
  34. Nagle R. B., Böcker W., Davis J. R., Heid H. W., Kaufmann M., Lucas D. O., Jarasch E. D. Characterization of breast carcinomas by two monoclonal antibodies distinguishing myoepithelial from luminal epithelial cells. J Histochem Cytochem. 1986 Jul;34(7):869–881. doi: 10.1177/34.7.2423579. [DOI] [PubMed] [Google Scholar]
  35. Nagle R. B., Lucas D. O., McDaniel K. M., Clark V. A., Schmalzel G. M. Paget's cells. New evidence linking mammary and extramammary Paget cells to a common cell phenotype. Am J Clin Pathol. 1985 Apr;83(4):431–438. doi: 10.1093/ajcp/83.4.431. [DOI] [PubMed] [Google Scholar]
  36. Nelson W. G., Sun T. T. The 50- and 58-kdalton keratin classes as molecular markers for stratified squamous epithelia: cell culture studies. J Cell Biol. 1983 Jul;97(1):244–251. doi: 10.1083/jcb.97.1.244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Pinkus H., Iwasaki T., Mishima Y. Outer root sheath keratinization in anagen and catagen of the mammalian hair follicle. A seventh distinct type of keratinization in the hair follicle: trichilemmal keratinization. J Anat. 1981 Aug;133(Pt 1):19–35. [PMC free article] [PubMed] [Google Scholar]
  38. REYNOLDS E. S. The use of lead citrate at high pH as an electron-opaque stain in electron microscopy. J Cell Biol. 1963 Apr;17:208–212. doi: 10.1083/jcb.17.1.208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Roop D. R., Hawley-Nelson P., Cheng C. K., Yuspa S. H. Keratin gene expression in mouse epidermis and cultured epidermal cells. Proc Natl Acad Sci U S A. 1983 Feb;80(3):716–720. doi: 10.1073/pnas.80.3.716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Roop D. R., Krieg T. M., Mehrel T., Cheng C. K., Yuspa S. H. Transcriptional control of high molecular weight keratin gene expression in multistage mouse skin carcinogenesis. Cancer Res. 1988 Jun 1;48(11):3245–3252. [PubMed] [Google Scholar]
  41. Schermer A., Galvin S., Sun T. T. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells. J Cell Biol. 1986 Jul;103(1):49–62. doi: 10.1083/jcb.103.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Schweizer J., Winter H. Keratin biosynthesis in normal mouse epithelia and in squamous cell carcinomas. mRNA-dependent alterations of the primary structure of distinct keratin subunits in tumors. J Biol Chem. 1983 Nov 10;258(21):13268–13272. [PubMed] [Google Scholar]
  43. Skerrow D., Skerrow C. J. Tonofilament differentiation in human epidermis, isolation and polypeptide chain composition of keratinocyte subpopulations. Exp Cell Res. 1983 Jan;143(1):27–35. doi: 10.1016/0014-4827(83)90105-2. [DOI] [PubMed] [Google Scholar]
  44. Stark H. J., Breitkreutz D., Limat A., Bowden P., Fusenig N. E. Keratins of the human hair follicle: "hyperproliferative" keratins consistently expressed in outer root sheath cells in vivo and in vitro. Differentiation. 1987;35(3):236–248. doi: 10.1111/j.1432-0436.1987.tb00174.x. [DOI] [PubMed] [Google Scholar]
  45. Stasiak P. C., Purkis P. E., Leigh I. M., Lane E. B. Keratin 19: predicted amino acid sequence and broad tissue distribution suggest it evolved from keratinocyte keratins. J Invest Dermatol. 1989 May;92(5):707–716. doi: 10.1111/1523-1747.ep12721500. [DOI] [PubMed] [Google Scholar]
  46. Steinert P. M., Rogers G. E. Characterization of the proteins of guinea-pig hair and hair-follicle tissue. Biochem J. 1973 Dec;135(4):759–771. doi: 10.1042/bj1350759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Steinert P. M. Structural features of the alpha-type filaments of the inner root sheath cells of the guinea pig hair follicle. Biochemistry. 1978 Nov 14;17(23):5045–5052. doi: 10.1021/bi00616a029. [DOI] [PubMed] [Google Scholar]
  48. Stoler A., Kopan R., Duvic M., Fuchs E. Use of monospecific antisera and cRNA probes to localize the major changes in keratin expression during normal and abnormal epidermal differentiation. J Cell Biol. 1988 Aug;107(2):427–446. doi: 10.1083/jcb.107.2.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Stromer M. H., Bendayan M. Arrangement of desmin intermediate filaments in smooth muscle cells as shown by high-resolution immunocytochemistry. Cell Motil Cytoskeleton. 1988;11(2):117–125. doi: 10.1002/cm.970110205. [DOI] [PubMed] [Google Scholar]
  50. Tozawa T., Ackerman A. B. Basal cell carcinoma with follicular differentiation. Am J Dermatopathol. 1987 Dec;9(6):474–482. doi: 10.1097/00000372-198712000-00002. [DOI] [PubMed] [Google Scholar]
  51. Tyner A. L., Fuchs E. Evidence for posttranscriptional regulation of the keratins expressed during hyperproliferation and malignant transformation in human epidermis. J Cell Biol. 1986 Nov;103(5):1945–1955. doi: 10.1083/jcb.103.5.1945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Vassar R., Rosenberg M., Ross S., Tyner A., Fuchs E. Tissue-specific and differentiation-specific expression of a human K14 keratin gene in transgenic mice. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1563–1567. doi: 10.1073/pnas.86.5.1563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Viac J., Staquet M. J., Thivolet J., Goujon C. Experimental production of antibodies against stratum corneum keratin polypeptides. Arch Dermatol Res. 1980;267(2):179–188. doi: 10.1007/BF00569104. [DOI] [PubMed] [Google Scholar]
  54. Weiss R. A., Eichner R., Sun T. T. Monoclonal antibody analysis of keratin expression in epidermal diseases: a 48- and 56-kdalton keratin as molecular markers for hyperproliferative keratinocytes. J Cell Biol. 1984 Apr;98(4):1397–1406. doi: 10.1083/jcb.98.4.1397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Woodcock-Mitchell J., Eichner R., Nelson W. G., Sun T. T. Immunolocalization of keratin polypeptides in human epidermis using monoclonal antibodies. J Cell Biol. 1982 Nov;95(2 Pt 1):580–588. doi: 10.1083/jcb.95.2.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. van Muijen G. N., Ruiter D. J., Franke W. W., Achtstätter T., Haasnoot W. H., Ponec M., Warnaar S. O. Cell type heterogeneity of cytokeratin expression in complex epithelia and carcinomas as demonstrated by monoclonal antibodies specific for cytokeratins nos. 4 and 13. Exp Cell Res. 1986 Jan;162(1):97–113. doi: 10.1016/0014-4827(86)90429-5. [DOI] [PubMed] [Google Scholar]

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