Melanogenesis is coupled to murine anagen: Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth

  • Andrzej Slominski
    Reprint requests to: Dr. Andrzej T. Slominski, Department of Microbiology, Immunology and Molecular Genetics, 47 New Scotland Avenue, A-68, Albany Medical College, Albany, NY 12208.
    Department of Microbiology, Immunology and Molecular Genetics, Albany Medical College, Albany, New York, U.S.A.
    Search for articles by this author
  • Ralf Paus
    Department of Dermatology, University Hospital R. Virchow, Freie Universität Berlin, D-1000 Berlin 65, Germany
    Search for articles by this author
      This paper is only available as a PDF. To read, Please Download here.


      Hair is actively pigmented only when it grows: the melanogenic activity of follicular melanocytes (MC) is strictly coupled to the anagen stage of the hair cycle. In catagen, melanin formation is switched off and is absent throughout telogen. The appearance of pigmentation is preceded, and further accompanied by, a time-frame-restricted, differential pattern of tyrosinase transcription, translation, and enzyme activities during the development of anagen follicles. In this speculative review, we argue that signals required for melanin synthesis and pigment transfer to bulb keratinocytes (KC) are intrinsic to the skin, rather than coming from the serum. First, the proopiomelanocortin (POMC) gene is expressed and translated during anagen, but is below the level of detectability in telogen; POMC is a precursor protein for adrenocorticotropin and melanotropins, which are potent regulators of MC proliferation and differentiation. Second, fibroblasts and KC produce factors that affect MC proliferation and differentiation. We suggest that signals regulating follicular MC activity partially derive from cutaneous cells expressing POMC. Vice versa, MC transfer to surrounding KC pigment granules with potent bioregulatory properties. MC also produce and secrete various signal molecules that can regulate mesenchymal and epithelial cell functions. Anagen-associated melanogenesis and the cyclic production of a pigmented hair shaft result from programmed and tightly coordinated epithelial-mesenchymal-neuroectodermal interactions, in which MC may act not only as pigmentary, but also as hair growth-regulatory cells.


      ET (endothelins), KC (keratinocytes), MC (melanocytes), MSH (melanotropins), POMC (proopiomelanocortins)


        • Chase HB
        Growth of the hair.
        Physiol Rev. 1954; 34: 113-126
        • Chase HB
        Induced melanocyte deactivation and reactivation in hair follicles.
        Adv Biol Skin. 1966; 8: 503-507
      1. Orfanos CE Happle R Hair and Hair Diseases. Springer-Verlag, Berlin, Heidelberg1990
        • Hardy MH
        The secret life of the hair follicle.
        Trend Genet. 1992; 8: 55-61
        • Paus R
        • Czarnetzki BM
        Neue Perspektiven in der Haarforschung: auf der Suche nach der “biologischen Uhr” des Haarzyklus.
        Hautarzt. 1992; 43: 264-271
      2. Silvers WK The Coat Colors of Mice. 3rd ed. A Model for Mammalian Gene Action and Interaction. Springer Verlag, New York1979
      3. Goldsmith LA Physiology, Biochemistry and Molecular Biology of the Skin. Oxford University Press, New York1991
        • Hearing VJ
        • Tsukamato K
        Enzymatic control of pigmentation in mammals.
        FASEB J. 1991; 5: 2902-2909
        • Pawelek J
        After Dopachrome?.
        Pigment Cell Res. 1991; 4: 53-62
        • Prota G
        Progress in the chemistry of melanins and related metabolites.
        Med Res Rev. 1988; 8: 525-556
        • Ortonne JP
        • Thivolet J
        Hair melanin and hair control.
        in: Orfanos CE Montagna W Stuttgen G Hair Research. Springer, Berlin1981
      4. Rook A Dawber RPR Diseases of the Hair and Scalp. Blackwell, Oxford1991
      5. Gilbert SF Developmental Biology. Sinauer, Sunderlund, MA1991
        • Billingham RE
        • Silvers WK
        A biologist's reflections on dermatology.
        J Invest Dermatol. 1971; 57: 227-240
        • Fitzpatrick TB
        • Brunet P
        • Kukita A
        The nature of hair pigment.
        in: Montagna W Ellis RA The Biology of Hair Growth. Academic Press, New York1958: 255-303
        • Sugiyama S
        Mode of redifferentiation and melanogenesis of melanocytes in mouse hair follicles.
        J Ultrastruc Res. 1979; 67: 40-54
        • Silver AF
        • Chase HB
        • Potten CS
        Melanocyte precursor cells in the hair follicle germ during the dormant stage (telogen).
        Experientia. 1969; 25: 299-301
        • Slominski A
        • Paus R
        • Costantino R
        Differential expression and activity of melanogenesis-related proteins during induced hair growth in mice.
        J Invest Dermatol. 1991; 96: 172-179
        • Hansen LS
        • Coggle JE
        • Charles MW
        The influence of the hair cycle on the thickness of mouse skin.
        Anat Rec. 1984; 210: 569-573
        • Paus R
        • Stenn KS
        • Link RE
        Telogen skin contains an inhibitor of hair growth.
        Br J Dermatol. 1990; 122: 777-784
        • Burnett JB
        • Holstein TJ
        • Quevedo WC
        Electrophoretic variations of tyrosinase in follicular melanocytes during the hair growth cycle in mice.
        J Exp Zool. 1969; 171: 369-379
        • Burchill SA
        • Virden R
        • Thody AJ
        Regulation of tyrosinase synthesis and its processing in the hair follicular melanocytes of the mouse during eumelanogenesis and pheomelanogenesis.
        J Invest Dermatol. 1989; 93: 236-240
        • Yaar M
        • Gilchrest BA
        Human melanocyte growth and differentiation: a decade of new data.
        J Invest Dermatol. 1991; 97: 611-617
      6. Eberle A The Melanotropins. 3rd ed. Chemistry, Physiology and Mechanism of Action. Karger, New York1988
      7. Hadley ME Endocrinology. Englewood Cliffs, Prentice Hall, New Jersey1988
        • Nordlund J
        • Abdel-Malek ZA
        • Boissy RE
        • Rheins LA
        Pigment cell biology: an historical review.
        J Invest Dermatol. 1989; 92 (suppl): 53S-61S
        • Granholm NH
        • Van Amerongen AW
        Effects of exogenous MSH on the transformation from phaeo- to eumelanogenesis within C57 BL-6J-Aya hairbulb melanocytes.
        J Invest Dermatol. 1991; 96: 78-84
        • Slominski A
        • Paus R
        • Mazurkiewicz J
        Proopiomelanocortin expression in the skin during induced hair growth in mice.
        Experientia. 1992; 48: 50-54
        • Slominski A
        • Paus R
        • Wortsman J
        Can some melanotropins modulate keratinocyte proliferation? (letter).
        J Invest Dermatol. 1991; 97: 747
        • Slominski A
        • Paus R
        • Mazurkiewicz J
        Pro-opiomelanocortin expression and potential function of pro-opiomelanocortin products during induced hair growth in mice.
        Ann NY Acad Sci. 1991; 642: 459-461
        • Amornisiripanitch S
        • Nordlund JJ
        Messenger mRNA specific for POMC identified in murine epidermal cells (abstr).
        J Invest Dermatol. 1989; 92: 395
        • Kock A
        • Schauer E
        • Schwarz T
        • Luger TA
        Neuropeptides such as MSH and ACTH are produced by human keratinocytes (abstr).
        J Invest Dermatol. 1990; 95: 476
        • Johansson O
        • Ljunberg A
        • Han SW
        • Vaalasti J
        Evidence for gammamelanocyte stimulating hormone containing nerves and neutrophilic granulocytes in the human skin by indirect immunofluorescence.
        J Invest Dermatol. 1991; 96: 852-856
        • Kock A
        • Schauer E
        • Urbanski A
        • Schwarz T
        • Luger T
        Melanotropic hormones (MSH) regulate cytokine production in normal human melanocytes (abstr).
        J Invest Dermatol. 1992; 98: 823
        • Halaban R
        • Langdon R
        • Birchall N
        • Cuono C
        • Baird A
        • Scott G
        • Moellmann G
        • McGuire J
        Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes.
        J Cell Biol. 1988; 107: 1611-1619
        • Krasagakis K
        • Garbe C
        • Kruger S
        • Orfanos CE
        Effects of interferons on cultured human melanocytes in vitro: interferon-beta but not -alpha or gamma inhibit proliferation and all interferons significantly modulate the cell phenotype.
        J Invest Dermatol. 1991; 97: 364-372
        • Morelli JG
        • Yohn JJ
        • Lyons MB
        • Murphy RC
        • Norris D
        Leukotriene C4 and TGF-alpha are stimulators of human melanocyte migration in vitro.
        J Invest Dermatol. 1992; 98: 290-295
        • Varani J
        • Mitra RS
        • McClenic BJ
        • Fligiel SEG
        • Inman DR
        • Dixit VM
        • Nickoloff BJ
        Modulation of fibronectin production in normal human melanocytes and malignant melanoma cells by interferon-gamma and tumor necrosis factor-alfa.
        Am J Pathol. 1989; 134: 827-836
        • Valyi-Nagy IT
        • Herlyn M
        Regulation of growth and phenotype of normal human melanocytes in culture.
        in: Nathanson L Melanoma Research: Genetics, Growth Factors, Metastases, and Antigens. Kluwer Academic Publishers, Boston1991: 85-101
        • Yada Y
        • Higuchi K
        • Imokawa G
        Effects of endothelins on signal transduction and proliferation in human melanocytes.
        J Biol Chem. 1991; 266: 18352-18357
        • Swope VP
        • Abdel-Malek Z
        • Kassem LM
        • Nordlund J
        Interleukin la and 6 and tumor necrosis factor-a are paracrine inhibitors of human melanocytes proliferation and melanogenesis.
        J Invest Dermatol. 1991; 96: 180-185
        • Slominski A
        • Paus R
        • Bomirski A
        Hypothesis: a possible role of the melatonin receptor in vitiligo.
        J Roy Soc Med. 1989; 82: 539-541
        • Slominski A
        • Paus R
        Are L-tyrosine and L-dopa hormone-like bioregulators?.
        J Theor Biol. 1990; 143: 123-138
      8. Bos JD Skin Immune System (SIS). CRC Press, Inc, Boca Raton, Florida1990
        • Morelli JG
        • Kincannon J
        • Yohn JJ
        • Zekman T
        • Weston WL
        • Norris D
        Leukotriene C4 and D4 as potent mitogens for cultured human neonatal melanocytes.
        J Invest Dermatol. 1992; 93: 719-722
        • Mosher DB
        • Fitzpatrick TB
        • Ortonne JP
        • Hori Y
        Disorders in pigmentation.
        in: Fitzpatrick TB Eisen AZ Wolff K Freedberg IM Austen K Dermatology in General Medicine. McGraw-Hill Book Company, New York1987: 794-876
        • Burchill SA
        • Thody AJ
        Dopaminergic inhibition of tyrosinase activity in hair follicular melanocytes of the mouse.
        J Endocrinol. 1986; 11: 223-237
        • Halata Z
        Touch organs in the hairy and glabrous skin of some mammals (an ultrastructural comparison).
        Neth J Zool. 1990; 40: 329-351
        • Mayer TC
        Tissue environmental influences on the development of melanoblasts in Steel mice.
        in: Slavkin HC Greulich RC Extracellular Matrix Influences on Gene Expression. Academic Press, New York1976: 555-560
        • Ranson M
        • Posen S
        • Mason RS
        Extracellular matrix modulates the function of human melanocytes but not melanoma cells.
        J Cell Physiol. 1988; 136: 281-288
        • McClenic BK
        • Mitra RS
        • Riser BL
        • Nickoloff BJ
        • Dixi VM
        • Varani J
        Production and utilization of extracellular matrix components by human melanocytes.
        Exp Cell Res. 1989; 180: 314-325
      9. Joseph M Lehrbuch der Haarkrankheiten. Johann Ambrosius Barth, Leipzig1921
        • Tobin DJ
        • Fenton DA
        • Kendall MD
        Ultrastructural observations on the hair bulb melanocytes and melanosomes in acute alopecia areata.
        J Invest Dermatol. 1990; 94: 803-807
        • Drager UC
        • Balkema GW
        Does melanin do more than protect from light?.
        Neurosci Res Suppl. 1987; 6: S75-S86
        • Slominski A
        • Goodman-Snitkoff G
        DOPA inhibits induced proliferative activity of murine and human lymphocytes.
        Anticancer Res. 1992; 12: 753-756
        • Kock A
        • Schwarz T
        • Luger TA
        The human melanocyte is an immunocompetent epidermal cell: production of immunomodulating cytokines (abstr).
        Arch Derm Res. 1991; 283: 56
        • Zachariae CO
        • Thestrup-Pedersen K
        • Matsushima K
        Expression and secretion of leukocyte chemotactic cytokines by normal human melanocytes and melanoma cells.
        J Invest Dermatol. 1991; 97: 593-597
        • Hashimoto K
        • Horikoshi T
        • Nishioka K
        • Yoshikawa K
        • Carter DM
        Plasminogen activator secreted by cultured human melanocytes.
        Br J Dermatol. 1986; 115: 205-209
        • Westgate GE
        • Crags RI
        • Gibson WT
        Immune priviledge in hair growth.
        J Invest Dermatol. 1991; 97: 417-420
        • Paus R
        • Link RE
        The psoriatic epidermal lesion and anagen hair growth may share the same “switch-on” mechanism.
        Yale J Biol Med. 1988; 61: 467-476
        • Paus R
        • Stenn KS
        • Link RE
        The induction of anagen hair follicle growth in telogen mouse skin by cyclosporine A administration.
        Lab Invest. 1989; 60: 365-369
        • Wong M
        • Jimbow K
        Selective cytotoxicity of N-acetyl-4-S-cysteaminylphenol on follicular melanocytes of black mice.
        Br J Dermatol. 1991; 124: 56-61
        • Li L
        • Paus R
        • Slominski A
        • Hoffman R
        Skin histoculture assay for studying the hair cycle.
        In Vitro Cell Dev Biol. 1992; 28A: 695-698
      10. Li L, Margolis LB, Paus R, Hoffmann RM: Hair shaft elongation, follicle growth and spontaneous regression in longpterm, spongegel supported histoculture of human scalp skin. Proc Natl Acad Sci (in press)