Hair Follicle Pigmentation
2005; Elsevier BV; Volume: 124; Issue: 1 Linguagem: Inglês
10.1111/j.0022-202x.2004.23528.x
ISSN1523-1747
AutoresAndrzej Słomiński, Jacobo Wortsman, Przemysław M. Płonka, Karin U. Schallreuter, Ralf Paus, Desmond J. Tobin,
Tópico(s)Dyeing and Modifying Textile Fibers
ResumoHair shaft melanin components (eu- or/and pheomelanin) are a long-lived record of precise interactions in the hair follicle pigmentary unit, e.g., between follicular melanocytes, keratinocytes, and dermal papilla fibroblasts. Follicular melanogenesis (FM) involves sequentially the melanogenic activity of follicular melanocytes, the transfer of melanin granules into cortical and medulla keratinocytes, and the formation of pigmented hair shafts. This activity is in turn regulated by an array of enzymes, structural and regulatory proteins, transporters, and receptors and their ligands, acting on the developmental stages, cellular, and hair follicle levels. FM is stringently coupled to the anagen stage of the hair cycle, being switched-off in catagen to remain absent through telogen. At the organ level FM is precisely coupled to the life cycle of melanocytes with changes in their compartmental distribution and accelerated melanoblast/melanocyte differentiation with enhanced secretory activity. The melanocyte compartments in the upper hair follicle also provides a reservoir for the repigmentation of epidermis and, for the cyclic formation of new anagen hair bulbs. Melanin synthesis and pigment transfer to bulb keratinocytes are dependent on the availability of melanin precursors, and regulation by signal transduction pathways intrinsic to skin and hair follicle, which are both receptor dependent and independent, act through auto-, para- or intracrine mechanisms and can be modified by hormonal signals. The important regulators are MC1 receptor its and adrenocorticotropic hormone, melanocyte stimulating hormone, agouti protein ligands (in rodents), c-Kit, and the endothelin receptors with their ligands. Melanin itself has a wide range of bioactivities that extend far beyond its determination of hair color. Hair shaft melanin components (eu- or/and pheomelanin) are a long-lived record of precise interactions in the hair follicle pigmentary unit, e.g., between follicular melanocytes, keratinocytes, and dermal papilla fibroblasts. Follicular melanogenesis (FM) involves sequentially the melanogenic activity of follicular melanocytes, the transfer of melanin granules into cortical and medulla keratinocytes, and the formation of pigmented hair shafts. This activity is in turn regulated by an array of enzymes, structural and regulatory proteins, transporters, and receptors and their ligands, acting on the developmental stages, cellular, and hair follicle levels. FM is stringently coupled to the anagen stage of the hair cycle, being switched-off in catagen to remain absent through telogen. At the organ level FM is precisely coupled to the life cycle of melanocytes with changes in their compartmental distribution and accelerated melanoblast/melanocyte differentiation with enhanced secretory activity. The melanocyte compartments in the upper hair follicle also provides a reservoir for the repigmentation of epidermis and, for the cyclic formation of new anagen hair bulbs. Melanin synthesis and pigment transfer to bulb keratinocytes are dependent on the availability of melanin precursors, and regulation by signal transduction pathways intrinsic to skin and hair follicle, which are both receptor dependent and independent, act through auto-, para- or intracrine mechanisms and can be modified by hormonal signals. The important regulators are MC1 receptor its and adrenocorticotropic hormone, melanocyte stimulating hormone, agouti protein ligands (in rodents), c-Kit, and the endothelin receptors with their ligands. Melanin itself has a wide range of bioactivities that extend far beyond its determination of hair color. agouti protein bone morphogenic proteins catechol-O-methyltransferase corticotropin releasing hormone cysteine protease cathepsin L dopachrome tautomerase dihydroxyindole dihydroxyindole carboxylic acid DHICA conversion factor dermal papilla electron paramagnetic resonance endoplasmic reticulum endothelin follicular melanogenesis L-3,4-dihydroxyphenylalanine melanocortin receptor 1 macrophage migration inhibitory factor microphtalmia-associated transcription factor melanogenesis-related proteins melanocyte stimulating hormone oculo-cutaneous albinism phenylalanine hydroxylase protease-activated receptor 2 reactive oxygen species stem cell factor trans-Golgi network tyrosinase-related protein Follicular pigmentation is under complex genetic control, as determined from studies in mostly murine models. In the mouse, coat color is regulated by more than 150 alleles at over 90 loci (Hearing, 1999Hearing V.J. Biochemical control of melanogenesis and melanosomal organization.J Investig Dermatol Symp Proc. 1999; 4: 24-28Abstract Full Text PDF PubMed Scopus (190) Google Scholar; Nakamura et al., 2002Nakamura M. Tobin D.J. Richards-Smith B. Sundberg J.P. Paus R. Mutant laboratory mice with abnormalities in pigmentation: Annotated tables.J Dermatol Sci. 2002; 28: 1-33https://doi.org/10.1016/S0923-1811(01)00158-XAbstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar) (S1) (Mouse Genome Database). Protein products of these loci have a wide array of cellular targets, and functions, acting as enzymes, structural proteins, transcriptional regulators, transporters, or receptors and their ligands (Hearing, 1999Hearing V.J. Biochemical control of melanogenesis and melanosomal organization.J Investig Dermatol Symp Proc. 1999; 4: 24-28Abstract Full Text PDF PubMed Scopus (190) Google Scholar; Slominski et al., 2004Slominski A. Tobin D.J. Shibahara S. Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation.Physiol Rev. 2004; 84: 1122-1155https://doi.org/10.1152/physrev.00044.2003Crossref Scopus (1471) Google Scholar) (S5). This organization allows control of melanin synthesis at all levels: cellular (follicular melanocyte), organ (hair follicle), and developmental steps (neural crest, melanoblast migration, targeting to skin, differentiation to melanocytes, and melanocyte proliferation and survival). In the adult hair follicle, pigmentation results from precise sequential interactions between follicular melanocytes, matrix keratinocytes, and dermal papilla (DP) fibroblasts (Slominski and Paus, 1993Slominski A. Paus R. Melanogenesis is coupled to murine anagen: Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth.J Invest Dermatol. 1993; 101: 90S-97Shttps://doi.org/10.1111/1523-1747.ep12362991Abstract Full Text PDF PubMed Scopus (269) Google Scholar). It involves the melanogenic activity of follicular melanocytes, the transfer of their product, melanin granules, into cortical and medullary keratinocytes, and the formation of pigmented hair shafts. Hair is actively pigmented only during the anagen stage of the hair cycle, to which the melanogenic activity of follicular melanocytes is stringently coupled; melanin formation is switched-off in catagen remaining absent through telogen (Slominski and Paus, 1993Slominski A. Paus R. Melanogenesis is coupled to murine anagen: Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth.J Invest Dermatol. 1993; 101: 90S-97Shttps://doi.org/10.1111/1523-1747.ep12362991Abstract Full Text PDF PubMed Scopus (269) Google ScholarS). Pigmentation lags behind the expression of melanogenesis-related proteins (MRP) that in turn exhibits a time-frame restricted, differential pattern of transcription, translation and functional activity during the development of anagen follicles (Slominski et al., 1991Slominski A. Paus R. Costantino R. Differential expression and activity of melanogenesis-related proteins during induced hair growth in mice.J Invest Dermatol. 1991; 96: 172-179https://doi.org/10.1111/1523-1747.ep12460956Abstract Full Text PDF PubMed Scopus (127) Google Scholar,Slominski et al., 1994Slominski A. Paus R. Plonka P. Maurer M. Chakraborty A. Pruski D. Lukiewicz S. Melanogenesis during the anagen-catagen-telogen transformation of the murine hair cycle.J Invest Dermatol. 1994; 102: 862-869https://doi.org/10.1111/1523-1747.ep12382606Abstract Full Text PDF PubMed Scopus (153) Google Scholar; Slominski and Paus, 1993Slominski A. Paus R. Melanogenesis is coupled to murine anagen: Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth.J Invest Dermatol. 1993; 101: 90S-97Shttps://doi.org/10.1111/1523-1747.ep12362991Abstract Full Text PDF PubMed Scopus (269) Google Scholar). Thus, follicular melanogenesis (FM) is characteristically cyclic in nature, as opposed to the continuous melanogenesis of epidermal pigmentation. Melanin synthesis and pigment transfer to bulb keratinocytes are to a large extent controlled by signals intrinsic to skin and represented by products of keratinocytes, immunocytes, fibroblasts, and endothelial cells (Slominski and Paus, 1993Slominski A. Paus R. Melanogenesis is coupled to murine anagen: Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth.J Invest Dermatol. 1993; 101: 90S-97Shttps://doi.org/10.1111/1523-1747.ep12362991Abstract Full Text PDF PubMed Scopus (269) Google Scholar; Slominski and Paus, 1993Slominski A. Paus R. Melanogenesis is coupled to murine anagen: Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth.J Invest Dermatol. 1993; 101: 90S-97Shttps://doi.org/10.1111/1523-1747.ep12362991Abstract Full Text PDF PubMed Scopus (269) Google Scholar; Tobin et al., 1999Tobin D.J. Slominski A. Botchkarev V. Paus R. The fate of hair follicle melanocytes during the hair growth in mice.J Investig Dermatol Symp Proc. 1999; 4: 323-332Abstract Full Text PDF PubMed Scopus (96) Google Scholar). Melanocytes can reciprocally affect the surrounding cells, e.g., by direct melanosome transfer (to keratinocytes), or by production and secretion of functional regulators (Slominski and Paus, 1993Slominski A. Paus R. Melanogenesis is coupled to murine anagen: Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth.J Invest Dermatol. 1993; 101: 90S-97Shttps://doi.org/10.1111/1523-1747.ep12362991Abstract Full Text PDF PubMed Scopus (269) Google Scholar). Thus, anagen-coupled melanogenesis and its regulatory network control hair growth and pigmentation, leaving the pigmented hair shaft (a uniquely mammalian trait) as a visible, long-lived record of complex epithelial–mesenchymal–neuroectodermal interactions. The melanocyte component of this tissue interactive cell system in hair follicles is more sensitive to aging influences than melanocytes in the epidermis, resulting in hair graying/canities; likely, this reflects differences in the epidermal and follicular microenvironments (Tobin and Paus, 2001Tobin D.J. Paus R. Graying: Gerontobiology of the hair follicle pigmentary unit.Exp Gerontol. 2001; 36: 29-54https://doi.org/10.1016/S0531-5565(00)00210-2Crossref PubMed Scopus (247) Google Scholar). Cutaneous melanocytes originate from the neural crest where lineage commitment is determined by microphthalmia-associated transcription factor (MITF), fibroblast growth factor-2, endothelin 3 (ET3), and others (Dupin and Le Douarin, 2003Dupin E. Le Douarin N.M. Development of melanocyte precursors from the vertebrate neural crest.Oncogene. 2003; 22: 3016-3023https://doi.org/10.1038/sj.onc.1206460Crossref PubMed Scopus (146) Google Scholar). Melanoblasts migrate from the neural crest (S2) and populate the basal layer of the epidermis and then non-randomly enter the developing hair follicles. Melanogenic melanocytes can be detected at all stages of hair morphogenesis, from hair germ stage onwards (Peters et al., 2002Peters E.M. Tobin D.J. Botchkareva N. Maurer M. Paus R. Migration of melanoblasts into the developing murine hair follicle is accompanied by transient c-Kit expression.J Histochem Cytochem. 2002; 50: 751-766Crossref PubMed Scopus (90) Google Scholar) (S2a). Melanoblasts expressing c-Kit migrate into the stem cell factor (SCF)-supplying hair follicle epithelium and differentiated c-Kit-positive melanocytes target the bulb when “SCF-positive” (S2a) (Peters et al., 2002Peters E.M. Tobin D.J. Botchkareva N. Maurer M. Paus R. Migration of melanoblasts into the developing murine hair follicle is accompanied by transient c-Kit expression.J Histochem Cytochem. 2002; 50: 751-766Crossref PubMed Scopus (90) Google Scholar). The importance of this signaling pair is evident from the ability of a Kit blocking antibody to induce apoptosis in murine follicular melanocytes (Ito et al., 1999Ito M. Kawa Y. Ono H. et al.Removal of stem cell factor or addition of monoclonal anti-c-Kit antibody induces apoptosis in murine melanocyte precursors.J Invest Dermatol. 1999; 112: 796-801https://doi.org/10.1046/j.1523-1747.1999.00552.xCrossref PubMed Scopus (82) Google Scholar). C-Kit-negative melanoblasts invade the outer root sheath and bulge region in the fully developed hair follicle (Peters et al., 2002Peters E.M. Tobin D.J. Botchkareva N. Maurer M. Paus R. Migration of melanoblasts into the developing murine hair follicle is accompanied by transient c-Kit expression.J Histochem Cytochem. 2002; 50: 751-766Crossref PubMed Scopus (90) Google Scholar). Post-natally, c-Kit is required during the hair growth cycle for activation of melanocyte, although in stem cell compartment appears to exhibit SCF/c-Kit independence (Botchkareva et al., 2001Botchkareva N.V. Khlgatian M. Longley B.J. Botchkarev V.A. Gilchrest B.A. Scf/c-Kit signaling is required for cyclic regeneration of the hair pigmentation unit.FASEB J. 2001; 15: 645-658Crossref PubMed Scopus (200) Google Scholar). In the fully developed human scalp, anagen follicle melanocytes can be assigned to distinct anatomic compartments of region-specific differentiation status (Figure 1). In the mature hair follicle, melanotic dopa (dihydroxyphenylalanine)-positive melanocytes are readily detectable in the basal layer of the infundibulum and around the upper DP; moderately differentiated melanocytes may also be detected in the basal layer of the sebaceous gland (Figure 1). Dopa-negative amelanotic melanocytes appear in the mid-to-lower outer root sheath. Some amelanotic dopa-negative melanocytes may also be distributed in the periphery of the bulb and the most proximal matrix. The presence of immature melanocytes (melanoblasts) has been clearly documented in the adult hair follicle (Horikawa et al., 1996Horikawa T. Norris D.A. Johnson T.W. et al.Dopa-negative melanocytes in the outer root sheath of human hair follicles express premelanosomal antigens but not a melanosomal antigen or the melanosome-associated glycoproteins tyrosinase, TRP-1, and TRP-2.J Invest Dermatol. 1996; 106: 28-35https://doi.org/10.1111/1523-1747.ep12326989Crossref PubMed Scopus (102) Google Scholar; Tobin and Bystryn, 1996Tobin D.J. Bystryn J.C. Different populations of melanocytes are present in hair follicles and epidermis.Pigment Cell Res. 1996; 9: 304-310Crossref PubMed Scopus (125) Google Scholar). All the dopa-positive cells, and also some dopa-negative melanocytes of the mid outer root sheath are (pre)melanosome gp100 positive (Horikawa et al., 1996Horikawa T. Norris D.A. Johnson T.W. et al.Dopa-negative melanocytes in the outer root sheath of human hair follicles express premelanosomal antigens but not a melanosomal antigen or the melanosome-associated glycoproteins tyrosinase, TRP-1, and TRP-2.J Invest Dermatol. 1996; 106: 28-35https://doi.org/10.1111/1523-1747.ep12326989Crossref PubMed Scopus (102) Google Scholar). Amelanotic hair follicle melanocytes are devoid of dopa-oxidase activity, although low levels of the tyrosinase protein itself may be detected in some cells (S3). Similarly, c-Kit and Bcl-2 reactive amelanotic melanocytes are present in this hair follicle compartment (Grichnik et al., 1995Grichnik J.M. Crawford J. Jimenez F. et al.Human recombinant stem-cell factor induces melanocytic hyperplasia in susceptible patients.J Am Acad Dermatol. 1995; 33: 577-583https://doi.org/10.1016/0190-9622(95)91274-6Abstract Full Text PDF PubMed Scopus (55) Google Scholar), but do not express the melanogenic enzymes TRP (tyrosinase-related protein)1 and TRP2 (Horikawa et al., 1996Horikawa T. Norris D.A. Johnson T.W. et al.Dopa-negative melanocytes in the outer root sheath of human hair follicles express premelanosomal antigens but not a melanosomal antigen or the melanosome-associated glycoproteins tyrosinase, TRP-1, and TRP-2.J Invest Dermatol. 1996; 106: 28-35https://doi.org/10.1111/1523-1747.ep12326989Crossref PubMed Scopus (102) Google Scholar). The hair bulb is the only site of pigment production for the hair shaft; it contains highly melanogenic melanocytes and a minor sub-population of poorly differentiated pigment cells (Tobin and Bystryn, 1996Tobin D.J. Bystryn J.C. Different populations of melanocytes are present in hair follicles and epidermis.Pigment Cell Res. 1996; 9: 304-310Crossref PubMed Scopus (125) Google Scholar). It has been proposed that amelanotic hair bulb melanocytes may represent “transient” melanocytes that migrate from precursor melanocytes stores in the upper outer root sheath (Tobin and Bystryn, 1996Tobin D.J. Bystryn J.C. Different populations of melanocytes are present in hair follicles and epidermis.Pigment Cell Res. 1996; 9: 304-310Crossref PubMed Scopus (125) Google Scholar; Nishimura et al., 2002Nishimura E.K. Jordan S.A. Oshima H. et al.Dominant role of the niche in melanocyte stem-cell fate determination.Nature. 2002; 416: 854-860https://doi.org/10.1038/416854aCrossref PubMed Scopus (707) Google Scholar) (S4). Melanogenically active melanocytes are restricted to the upper hair matrix of the anagen hair follicle, below the pre-cortical keratinocyte population, correlating with the anagen transfer of melanin predominantly to the hair shaft cortex, less to the medulla, and, only rarely to the hair cuticle. Melanogenically active hair bulb melanocytes form functional units with neighboring immature pre-cortical keratinocytes that receive melanized secretory granules and ultimately form the pigmented hair shaft. The intimate nature of the relationship between bulbar melanocytes and the DP is evidenced by their separation via only a very thin and permeable basal lamina at the interface between the matrix and the mesenchymal DP. A common biochemical apparatus determines both follicular and epidermal melanogenesis (Fig S1), initiated by either hydroxylation of L-phenylalanine to L-tyrosine (Schallreuter et al., 1998aSchallreuter K. Slominski A. Pawelek J.M. Jimbow K. Gilchrest B.A. What controls melanogenesis?.Exp Dermatol. 1998; 7: 143-150Crossref PubMed Scopus (35) Google Scholar) or directly from L-tyrosine (Lerner and Fitzpatrick, 1950Lerner A.B. Fitzpatrick T.B. Biochemistry of melanin formation.Physiol Rev. 1950; 30: 1-126PubMed Google Scholar). Melanocyte melanogenesis therefore requires direct transport of L-tyrosine from the extracellular space (S5), or intracellular hydroxylation of L-phenylalanine by phenylalanine hydroxylase (PAH) (EC 1.14.16.1) (Schallreuter et al., 1998aSchallreuter K. Slominski A. Pawelek J.M. Jimbow K. Gilchrest B.A. What controls melanogenesis?.Exp Dermatol. 1998; 7: 143-150Crossref PubMed Scopus (35) Google Scholar). The latter depends on the essential cofactor (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH4), which melanocytes have full capacity for synthesis de novo, and for regulation of its recycling (Schallreuter et al., 1997Schallreuter K.U. Schulz-Douglas V. Bunz A. Beazley W.D. Korner C. Pteridines in the control of pigmentation.J Invest Dermatol. 1997; 109: 31-35https://doi.org/10.1111/1523-1747.ep12276418Crossref PubMed Scopus (38) Google Scholar). 6BH4 may act as an allosteric inhibitor of tyrosinase and its abiogenic isomer, 7BH4, may inhibit PAH (S6). Tyrosinase (EC 1.14.18.1), the product of the c locus, catalyzes the hydroxylation of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-dopa), which is followed by its oxidation to dopaquinone (common step in the eu- and pheomelanogenic pathways) (Hearing, 1999Hearing V.J. Biochemical control of melanogenesis and melanosomal organization.J Investig Dermatol Symp Proc. 1999; 4: 24-28Abstract Full Text PDF PubMed Scopus (190) Google Scholar) (S7). Alternative mechanisms for L-dopa formation are represented by the reduction of L-dopaquinone back to L-dopa (Cooksey et al., 1997Cooksey C.J. Garratt P.J. Land E.J. Pavel S. Ramsden C.A. Riley P.A. Smit N.P. Evidence of the indirect formation of the catecholic intermediate substrate responsible for the autoactivation kinetics of tyrosinase.J Biol Chem. 1997; 272: 26226-26235Crossref PubMed Scopus (309) Google Scholar), or even by a direct hydroxylation of tyrosine by tyrosine hydroxylase isoform I (TH I, EC 1.14.16.2) (Marles et al., 2003Marles L.K. Peters E.M. Tobin D.J. Hibberts N.A. Schallreuter K.U. Tyrosine hydroxylase isoenzyme I is present in human melanosomes: A possible novel function in pigmentation.Exp Dermatol. 2003; 12: 61-70https://doi.org/10.1034/j.1600-0625.2003.120108.xCrossref PubMed Scopus (53) Google Scholar; Gillbro et al., 2004Gillbro J.M. Marles L.K. Hibberts N.A. Schallreuter K.U. Autocrine catecholamine synthesis and the beta 2 adrenoceptor signal promote pigmentation in human epidermal melanocytes.J Invest Dermatol. 2004; 123: 346-353Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) (T1). Once L-dopa is formed, melanogenesis can proceed further through oxido-reduction reactions and intramolecular transformations occurring spontaneously, at rates determined by local concentrations of hydrogen ion, metal cations, thiols and other reducing agents, hydrogen peroxide, and oxygen (S7, S8). In the eumelanogenic pathway, the velocity and specificity of the reactions are regulated by the TRP, of which the most important is tyrosinase (also catalyzes the oxidation of dihydroxyindole (DHI)) (Korner and Pawelek, 1982Korner A. Pawelek J. Mammalian tyrosinase catalyzes three reactions in the biosynthesis of melanin.Science. 1982; 217: 1163-1165Crossref PubMed Scopus (479) Google Scholar; Hearing, 1999Hearing V.J. Biochemical control of melanogenesis and melanosomal organization.J Investig Dermatol Symp Proc. 1999; 4: 24-28Abstract Full Text PDF PubMed Scopus (190) Google Scholar) (S7). Tyrosinase protein structure is highly conserved among different species and shows high homology with other TRP including TRP1, a product of TYRP1 (human) or b (mouse) locus and TRP2 product of TYRP2/DCT (dopachrome tautomerase) (human), and slaty locus (mice). The gene sequences for these proteins have been established, and post-transcriptional processing of the corresponding mRNA generates several alternatively spliced products (reviewed in (Slominski et al., 2004Slominski A. Tobin D.J. Shibahara S. Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation.Physiol Rev. 2004; 84: 1122-1155https://doi.org/10.1152/physrev.00044.2003Crossref Scopus (1471) Google Scholar)). In mice but not humans, TRP1 acts as a 5,6 dihydroxyindole carboxylic acid (DHICA) oxidase to generate indole-5,6-quinone-carboxylic acid (S5, S9). In humans, it can exhibit tyrosine hydroxylase activity at low concentrations of substrate (Sarangarajan and Boissy, 2001Sarangarajan R. Boissy R.E. Tyrp1 and oculocutaneous albinism type 3.Pigment Cell Res. 2001; 14: 437-444https://doi.org/10.1034/j.1600-0749.2001.140603.xCrossref PubMed Scopus (88) Google Scholar). TRP1 appears to be important for eumelanogenesis, as suggested by its lack or defective expression in pheomelanogenic cells (Hearing, 1999Hearing V.J. Biochemical control of melanogenesis and melanosomal organization.J Investig Dermatol Symp Proc. 1999; 4: 24-28Abstract Full Text PDF PubMed Scopus (190) Google Scholar). It also appears to ensure the appropriate processing of tyrosinase, stabilization of its enzymatic activity, and maintenance of melanosome structural integrity (Hearing, 1999Hearing V.J. Biochemical control of melanogenesis and melanosomal organization.J Investig Dermatol Symp Proc. 1999; 4: 24-28Abstract Full Text PDF PubMed Scopus (190) Google Scholar; Sarangarajan and Boissy, 2001Sarangarajan R. Boissy R.E. Tyrp1 and oculocutaneous albinism type 3.Pigment Cell Res. 2001; 14: 437-444https://doi.org/10.1034/j.1600-0749.2001.140603.xCrossref PubMed Scopus (88) Google Scholar) (S9). TRP2//DCT can act as DCT (EC 5.3.2.3) catalyzing transformation of dopachrome to DHICA (S5). TYR-2 can also stabilize tyrosinase activity and has recently been shown to support melanocyte survival (S9). Other enzymatic regulators of melanogenesis include PMEL17 protein (HMB-45/gp100/silver locus), catechol-O-methyltransferase (COMT) (EC 2.1.1.6), peroxidase (EC 1.11.1.7), and macrophage migration inhibitory factor (MIF) (Hearing, 1999Hearing V.J. Biochemical control of melanogenesis and melanosomal organization.J Investig Dermatol Symp Proc. 1999; 4: 24-28Abstract Full Text PDF PubMed Scopus (190) Google Scholar) (S5, S7). It has been proposed that PMEL17 catalyzes the polymerization of DHICA to melanin, and that PMEL17/GP100 may act in melanosomes as scaffold for the deposition of melanin, and for stabilizing melanin intermediates (S5, S9). COMT is responsible for O-methylation of dopa and its DHI intermediates, whereas peroxidase catalyzes the oxidation of DHI and DHICA (S5, S7). MIF expresses D-dopachrome tautomerase activity and transforms D-dopachrome, dopaminechrome or its derivatives to their indole compounds (S9). Enzymes indirectly affecting melanogenesis are glutathione reductase and glutathione peroxidase that regulate glutathione reduced/oxidized levels (S5, S7), and catalase which regulates hydrogen peroxide removal (Schallreuter et al., 1998aSchallreuter K. Slominski A. Pawelek J.M. Jimbow K. Gilchrest B.A. What controls melanogenesis?.Exp Dermatol. 1998; 7: 143-150Crossref PubMed Scopus (35) Google Scholar). Synthesis of pheomelanin starts with the conjugation of dopaquinone with cysteine or glutathione yielding cysteinyldopa and glutathionyldopa (S7). After oxidation, cysteinyldopa undergoes ring closure to yield 1,4-benzothiazinylalanines that may couple through a peroxidase/H2O2-promoted reaction or tyrosinase-catalyzed oxidation; the multistep process ends with the formation of pheomelanin (S7). An alternative route for cysteinyldopa formation is represented by the conjugation of dopaquinone with glutathione followed by glutamyltranspeptidase catalyzed hydrolysis of the resultant glutathionyldopa. The main regulatory mechanism switch from eu- to pheomelanogenesis employs dopaquinone as a key molecule controlling the activity of glutathione reductase and blocking pheomelanogenesis at high tyrosinase activity, and high eumelanogenesis rate (Oyehaug et al., 2002Oyehaug L. Plante E. Vage D.I. Omholt S.W. The regulatory basis of melanogenic switching.J Theor Biol. 2002; 215: 449-468https://doi.org/10.1006/jtbi.2001.2521Crossref PubMed Scopus (34) Google Scholar). The velocity of post-cysteinyldopa steps of melanogenesis is increased by peroxidase and tyrosinase that are involved in the transformation of benzothiazinylalanines (S7). In melanocytes, melanin synthesis is restricted to melanosomes that are structurally assembled via a process resembling lysosome biogenesis (Jimbow et al., 2000Jimbow K. Park J. Kato F. Hirosaki K. Toyofuku K. Hua C. Yamashita T. Assembly, target-signaling and the intracellular transport of tyrosinase gene family proteins in the initial stages of melanosome biogenesis.Pigment Cell Res. 2000; 13: 222-229https://doi.org/10.1034/j.1600-0749.2000.130403.xCrossref PubMed Scopus (109) Google Scholar; Marks and Seabra, 2001Marks M. Seabra M. The melanosome: Membrane dynamics in black and white.Nat Rev Mol Cell Biol. 2001; 2: 1-11https://doi.org/10.1038/35048018Crossref Google Scholar) (S10, S11). Although the exact sequence of events leading to melanosome formation is under intense research, there is a consensus that melanosome structure correlates with the type of melanin produced—eumelanosomes are elliptical and contain fibrillar matrix, whereas pheomelanosome shape is variable but predominantly spherical and contain a vesiculoglobular matrix. Morphologically their development and maturation proceeds via 4 stages: stage I characterized by early matrix organization; stage II when this matrix is complete, and melanin formation has not yet commenced in eumelanosomes (but is already detectable in pheomelanosomes); stage III typified by melanin deposition; and stage IV where the organelle is saturated with melanin. Recent evidence suggests that cleavage of the melanocyte-specific integral membrane glycoprotein PMEl17 by prohormone convertases contributes to melanosome biogenesis by regulating the nucleation of intralumenal fibrous striations onto which melanin is later deposited (Berson et al., 2003Berson J.F. Theos A.C. Harper D.C. Tenza D. Raposo G. Marks M.S. Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis.J Cell Biol. 2003; 161: 521-533Crossref PubMed Scopus (224) Google Scholar). Melanosome biogenesis appears to be essentially similar in follicular and epidermal melanocytes. Black-hair follicles melanocytes contain the largest number of melanosomes (eumelanosomes) that are electron-dense. Brown-hair bulb melanosomes are somewhat smaller, in blonde hair melanosomes are poorly melanized, and, often only the melanosomal matrix is visible. Red-hair pheomelanosomes contain a vesicular matrix, but melanin is deposited irregularly as flocculent material. Both eumelanogenic and pheomelanogenic melanosomes can co-exist in the same human cell (Inazu and Mishima, 1993Inazu M. Mishima Y. Detection of eumelanogenic and pheomelanogenic melanosomes in the same normal human melanocyte.J Invest Dermatol. 1993; 100: 17
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