Human hair melanins: what we have learned and have not learned from mouse coat color pigmentation (original) (raw)
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Tyrosinase Depletion Prevents the Maturation of Melanosomes in the Mouse Hair Follicle
PloS one, 2015
The mechanisms that lead to variation in human skin and hair color are not fully understood. To better understand the molecular control of skin and hair color variation, we modulated the expression of Tyrosinase (Tyr), which controls the rate-limiting step of melanogenesis, by expressing a single-copy, tetracycline-inducible shRNA against Tyr in mice. Moderate depletion of TYR was sufficient to alter the appearance of the mouse coat in black, agouti, and yellow coat color backgrounds, even though TYR depletion did not significantly inhibit accumulation of melanin within the mouse hair. Ultra-structural studies revealed that the reduction of Tyr inhibited the accumulation of terminal melanosomes, and inhibited the expression of genes that regulate melanogenesis. These results indicate that color in skin and hair is determined not only by the total amount of melanin within the hair, but also by the relative accumulation of mature melanosomes.
Melanocyte biology and skin pigmentation
Nature, 2007
Melanocytes can absorb ultraviolet radiation (UVR) and survive considerable genotoxic stress. The skin is the main barrier to the external environment, and relies on melanocytes to provide, among other things, photoprotection and thermoregulation by producing melanin. The degree of pigment production manifests as skin 'phototype' (skin colour and ease of tanning) 1 and is the most useful predictor of human skin cancer risk in the general population. The colours we see in feathers, fur and skin are largely determined by melanocytes. In addition to carotenoids and haemoglobin, melanin is the main contributor to pigmentation. There are two main types of melanin-red/yellow pheomelanin and brown/black eumelanin. Melanincontaining granules are known as melanosomes and are exported from melanocytes to adjacent keratinocytes, where most pigment is found. As a result, pigmentation differences can arise from variation in the number, size, composition and distribution of melanosomes, whereas melanocyte numbers typically remain relatively constant (Fig. 1a, b). Mutations affecting pigmentation have been identified in many species because they are easily recognizable. Such mutants can be categorized into four groups: hypopigmentation and hyperpigmentation, with or without altered melanocyte number. These phenotypic distinctions have afforded the opportunity to easily classify genes affecting the melanocyte lineage, with respect to viability or differentiation (or both). Some of these mutants function in non-cell-autonomous manner, thereby further revealing cellcell communication pathways of physiological importance. Collectively, pigmentation or coat colour mutants have become an invaluable resource for the analysis of melanocyte differentiation and as a model for the broader fields of neural-crest development and mammalian genetics. There are two discrete melanocytic populations in hair follicles: melanocyte stem cells and their differentiated progeny, which reside in geographically distinct locations to comprise a follicular unit that is tightly linked to the surrounding keratinocyte population. Hair follicle melanocyte stem cells have important roles in both normal hair pigmentation and senile hair greying, and specific genetic defects have shed further light on the survival properties of this cell population. This review summarizes how pigmentation is regulated at the molecular level and how the tanning response provides protection against damage and skin cancer. We discuss recent advances in our knowledge of the genes involved in these processes and how they affect skin and hair colour. We also cover the developmental origin of melanocytes and how they are maintained by melanoblast stem cells, whose eventual depletion may contribute to hair greying. Finally, we detail some questions that research into melanocyte biology hopes to address in the future.
Diversity of human hair pigmentation as studied by chemical analysis of eumelanin and pheomelanin
Journal of the European Academy of Dermatology and Venereology, 2011
Hair colour is one of the most conspicuous phenotypes in humans, ranging from black, brown, blond to red. This diversity arises mostly from the quantity and ratio of the black-dark brown eumelanin and the reddish-brown pheomelanin. To study the chemical basis underlying the diversity of hair colour, we have developed several chemical methods to quantify those two pigments. Alkaline H 2 O 2 oxidation affords pyrrole-2,3,5-tricarboxylic acid (PTCA) as a eumelanin marker and thiazole-2,4,5-tricarboxylic acid (TTCA) as a pheomelanin marker. Pheomelanin can also be analysed as 4-amino-3-hydroxyphenylalanine (4-AHP) after hydroiodic acid hydrolysis. Using those methods, we evaluated the contents of eumelanin and pheomelanin (the 'chemical' phenotype) in human hairs of black, dark brown, brown, light brown, blond and red colour (the 'visual' phenotype). Eumelanin contents decrease in that order, with a trace but constant level of pheomelanin, except for red hair which contains about equal levels of pheomelanin and eumelanin. Thus, the chemical phenotype correlates well with the visual phenotype. The genotype of melanocortin-1 receptor (MC1R), a gene regulating the red hair phenotype, is predictive of hair melanin expressed as the log value of eumelanin to pheomelanin ratio, with a dosage effect evident. Hair melanin contents were also analysed in patients with various hypopigmentary disorders including Hermansky-Pudlak syndrome, Menkes disease, proopiomelanocortin deficiency, cystinosis, malnutrition and trace metal deficiency. The chemical phenotype helped evaluate the precise effects of each disease on pigmentation. In studies of human hair, the chemical phenotype will find more and more application as an objective measure of pigmentation.
Physiological factors that regulate skin pigmentation
BioFactors, 2009
More than 150 genes have been identified that affect skin color either directly or indirectly, and we review current understanding of physiological factors that regulate skin pigmentation. We focus on melanosome biogenesis, transport and transfer, melanogenic regulators in melanocytes, and factors derived from keratinocytes, fibroblasts, endothelial cells, hormones, inflammatory cells, and nerves. Enzymatic components of melanosomes include tyrosinase, tyrosinase‐related protein 1, and dopachrome tautomerase, which depend on the functions of OA1, P, MATP, ATP7A, and BLOC‐1 to synthesize eumelanins and pheomelanins. The main structural component of melanosomes is Pmel17/gp100/Silv, whose sorting involves adaptor protein 1A (AP1A), AP1B, AP2, and spectrin, as well as a chaperone‐like component, MART‐1. During their maturation, melanosomes move from the perinuclear area toward the plasma membrane. Microtubules, dynein, kinesin, actin filaments, Rab27a, melanophilin, myosin Va, and Slp2...
Acid hydrolysis reveals a low but constant level of pheomelanin in human black to brown hair
Pigment Cell & Melanoma Research, 2017
We previously reported a constant ratio of the benzothiazole-pheomelanin marker thiazole-2,4,5-tricarboxylic acid (TTCA) to the eumelanin marker pyrrole-2,3,5-tricaboxylic acid (PTCA) in eumelanic, black human hair. A constant level (20-25%) of benzothiazole-type pheomelanin was recently demonstrated in human skin with varying concentrations of melanin. Therefore, in this study, we aimed to investigate the origin of pheomelanin markers in black to brown human hair by developing a method to remove protein components from hair by heating with 6 M HCl at 110˚C for 16 h. For comparison, synthetic melanins were prepared by oxidizing mixtures of varying ratios of dopa and cysteine with tyrosinase. Hair melanins and synthetic melanins were subjected to acid hydrolysis followed by alkaline H 2 O 2 oxidation. The results show that the hydrolysis Accepted Article This article is protected by copyright. All rights reserved. leads to decarboxylation of the 5,6-dihydroxyindole-2-carboxylic acid moiety in eumelanin and the benzothiazole moiety in pheomelanin and that eumelanic human hair contains 11 to 17% benzothiazole-type pheomelanin. Significance The results of this study confirmed the presence of a low but constant level of benzothiazole-type pheomelanin in black to brown human hair. One advantage of this method of melanin characterization is that acid hydrolysis removes protein and low molecular weight components in tissue samples, and thus gives more simplified HPLC chromatograms compared with conventional H 2 O 2 oxidation. This method is useful not only to characterize melanins but also to confirm the presence of trace levels of eumelanin and pheomelanin in a variety of tissues and fossil samples.
Red hair, fair skin and melanoma - melanocortin 1 receptor
Experimental Dermatology, 2008
The peripheral nervous system comprises the autonomic and sensory (afferent) nervous systems. Major advances in our understanding of the autonomic and sensory transmission and function include the recognition of the phenotypic expression of a variety of transmitters and modulators that often coexist in individual neurons, the concept of co-transmission and chemical coding, the evidence for local effector functions of primary afferent nerves, and the discovery of plasticity of both the autonomic and the sensory nervous system during development, aging, diseases states, and inflammation. Co-transmission or plurichemical transmission, which indicates the release of more than one chemical messenger from the same neuron, enables autonomic and sensory neurons to exert a fine and highly regulated control of various functions such as circulation and immune response. The concept of chemical coding, in which the combination of transmitters/modulators is established, allows the identification of functional classes of neurons with their projections and targets. In addition to transmitters and modulators, autonomic and sensory neurons express multiple receptors, including G-proteincoupled and ion-gated receptors, further supporting the complexity of autonomic and sensory transmission and function. Autonomic neurons regulate the internal environment and maintain multiple homeostatic functions, and sensory neurons act as receptive structures that activate their targets in response to stimulation but also exert effector functions including the control of blood flow and vascular permeability, maintenance of mineralized tissue, and regulation of gene expression.
Pigment Cell Research, 2001
Melanocytes produce two chemically distinct types of melanin pigments, eumelanin and pheomelanin. These pigments can be quantitatively analyzed by acidic permanganate oxidation or reductive hydrolysis with hydriodic acid to form pyrrole-2,3,5-tricarboxylic acid or aminohydroxyphenylalanine, respectively. About 30 coat color genes in mice have been cloned, and functions of many of those genes have been elucidated. However, little is known about the interacting functions of these loci. In this study, we used congenic mice to eliminate genetic variability, and analyzed eumelanin and pheomelanin contents of hairs from mice mutant at one or more of the major pigment loci, i.e., the albino (C) locus that encodes tyrosinase, the slaty (Slt) locus that encodes tyrosinase-related protein 2 (TRP2 also known as dopachrome tautomerase, DCT), the brown (B) locus that encodes TRP1, the silver (Si) locus that encodes a melanosomal silver protein, the agouti (A) locus that encodes agouti signaling protein (ASP), the extension (E) locus that encodes melanocortin-1 receptor, and the mahogany (Mg) locus that encodes attractin. We also measured total melanin contents after solubilization of hairs in hot Soluene-350 plus water. Hairs were shaved from 2-3-month-old congenic C57BL/6J mice. The chinchilla (c(ch)) allele is known to encode tyrosinase, whose activity is about one third that of wild type (C). Phenotypes of chinchilla (c(ch)/c(ch)) mice that are wild type or mutant at the brown and/or slaty, loci indicate that functioning TRP2 and TRP1 are necessary, in addition to high levels of tyrosinase, for a full production of eumelanin. The chinchilla allele was found to reduce the amount of pheomelanin in lethal yellow and recessive yellow mice to less than one fifth of that in congenic yellow mice that were wild type at the albino locus. This indicates that reduction in tyrosinase activity affects pheomelanogenesis more profoundly compared with eumelanogenesis. Hairs homozygous for mutation at the slaty locus contain 5,6-dihydroxyindole-2-carboxylic acid (DHICA)-poor melanin, and this chemical phenotype was retained in hairs that were mutant at both the brown locus and the slaty locus. Hair from mice mutant at the brown locus, but not at the slaty locus, do not contain DHICA-poor melanin. This indicates that the proportion of DHICA in eumelanin is determined by TRP2, but not by TRP1. Mutation at the slaty locus (Slt(lt)) was found to have no effect on pheomelanogenesis, supporting a role of TRP2 only in eumelanogenesis. The mutation at silver (si) locus showed an effect similar to brown, a partial suppression of eumelanogenesis. The mutation at mahogany (mg) locus partially suppressed the effect of lethal yellow (Ay) on pheomelanogenesis, supporting a role of mahogany in interfering with agouti signaling. These results show that combination of double mutation study of congenic mice with chemical analysis of melanins is useful in evaluating the interaction of pigment gene functions.
Comparison of Structural and Chemical Properties of Black and Red Human Hair Melanosomes¶
Photochemistry and Photobiology, 2007
Melanosomes in black and red human hair are isolated and characterized by various chemical and physical techniques. Different yields of 4-amino-hydroxyphenolanaline by HI hydrolysis (a marker for pheomelanin) and pyrrole-2,3,5tricarboxylic acid by KMn04/H+ oxidation (a marker for eumelanin) indicate that the melanosomes in black hair are eumelanosomes, whereas those in red hair are mainly pheomelanosomes. Atomic force microscopy reveals that eumelanosomes and pheomelanosomes have ellipsoidal and spherical shapes, respectively. Eumelanosomes maintain structural integrity upon extraction from the keratin matrix, whereas pheomelanosomes tend to fall apart. The black-hair eumelanosomes have an average of 14.6 zk 0.5% amino acids content, which is attributed to the internal proteins entrapped in the melanosomes granules. The red-hair melanosomes contain more than 44% of amino acid content even after extensive proteolytic digestion. This high content of amino acids and the poorly reserved integrity of red-hair melanosomes suggest that some proteins are possibly covalently bonded with the melanin constituents in addition to those that are entrapped inside the melanin species. Soluene solubilization assay indicates the absorbance of melanin per gram of sample, adjusted for the amino acid content, is a factor of 2.9 greater for the black-hair melanosomes than the red-hair melanosomes. Metal analysis reveals significant amounts of diverse heavy metal ions bound to the two types of melanosomes. The amount of Cu(I1) and Zn(I1) are similar but Fe(II1) content is four times higher in the red-hair melanosomes. 13C solid-state nuclear magnetic resonance spectra and infrared spectra are presented and are shown to be powerful techniques qPosted on the website on 25 October 2004. -8655/05 for discerning differences in the amino acid contents, the 5,6dihydroxyindole-2-carboxylic acid:5,6-dihydroxyindole ratio, and the degree of cross-linking in the pigment. Excellent agreement is observed between these spectral results and the chemical degradation data.
Experimental Cell Research, 2001
The skin pigment melanin is produced in melanocytes in highly specialized organelles known as melanosomes. Melanosomes are related to the organelles of the endosomal/lysosomal pathway and can have a low internal pH. In the present study we have shown that melanin synthesis in human pigment cell lysates is maximal at pH 6.8. We therefore investigated the role of intramelanosomal pH as a possible control mechanism for melanogenesis. To do this we examined the effect of neutralizing melanosomal pH on tyrosinase activity and melanogenesis in 11 human melanocyte cultures and in 3 melanoma lines. All melanocyte cultures (9 of 9) from Caucasian skin as well as two melanoma cell lines with comparable melanogenic activity showed rapid (within 24 h) increases in melanogenesis in response to neutralization of melanosomal pH. Chemical analysis of total melanin indicated a preferential increase in eumelanin production. Electron microscopy revealed an accumulation of melanin and increased maturation of melanosomes in response to pH neutralization. In summary, our findings show that: (i) near neutral melanosomal pH is optimal for human tyrosinase activity and melanogenesis; (ii) melanin production in Caucasian melanocytes is suppressed by low melanosomal pH; (iii) the ratio of eumelanin/phaeomelanin production and maturation rate of melanosomes can be regulated by melanosomal pH. We conclude that melanosomal pH is an essential factor which regulates multiple stages of melanin production. Furthermore, since we have recently identified that pink locus product (P protein) mediates neutralization of melanosomal pH, we propose that P protein is a key control point for skin pigmentation. We would further propose that the wide variations in both constitutive and facultative skin pigmentation seen in the human population could be associated with the high degree of P-locus polymorphism.