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Melanocyte Biology 65 Jean L PIGMENTARY DISORDERS SECTION 10 Melanocyte Biology 65 Jean L. Bolognia and Seth J. Orlow In the inner ear, particularly in the stria vascularis, melanocytes are Key features thought to play a role in the development of hearing. Aberrant migra­ ■ The major determinant of normal skin color is the activity of tion or survival of melanocytes within the inner ear, the iris, and melanocytes, i.e. the quantity and quality of pigment production, midportions of the forehead and extremities explains the presence of not the density of melanocytes congenital deafness, heterochromia irides, and patches of leukoderma, ■ Melanocytes contain a unique intracytoplasmic organelle, the respectively, in patients with Waardenburg syndrome, the classic neuro­ melanosome, which is the site of melanin synthesis and deposition cristopathy. Also, aberrant migration or survival of enteric ganglion cells, another neural crest­derived cell population, provides an explana­ ■ Compared with lightly pigmented skin, darkly pigmented skin has tion for the association of aganglionic megacolon (Hirschsprung disease) melanosomes that contain more melanin and are larger; once with Waardenburg syndrome or rarely piebaldism. transferred to keratinocytes, the melanosomes are singly dispersed The survival and migration of neural crest­derived cells during and degraded more slowly embryogenesis depends upon interactions between specific receptors on ■ Tyrosinase is the key enzyme in the melanin biosynthetic pathway their cell surface and extracellular ligands. For example, KIT ligand ■ Two major forms of melanin are produced in melanocytes: (also known as steel factor or stem cell growth factor) binds to the brown–black eumelanin and yellow–red pheomelanin transmembrane KIT receptor on melanocytes and melanocyte precur­ ■ The production of eumelanin versus pheomelanin is influenced by sors (melanoblasts) (Figs 65.2 & 65.3); melanoblasts require expression the binding of melanocyte stimulating hormone to the of the KIT receptor in order to maintain their normal chemotactic melanocortin 1 receptor migration directed by production of KIT ligand by the dermamyotome. Heterozygous germline mutations in KIT that decrease the ability of the KIT receptor to be activated by KIT ligand are responsible for human piebaldism, whereas in mice, mutations in either kit or steel can lead to white spotting. In the developing embryo, melanoblasts expressing endothelin receptor type B (EDNRB) are stimulated to INTRODUCTION migrate by endothelin­3 (ET3 [EDN3]), which is produced by the ecto­ derm and dermamyotome. Mutations in one or both copies of EDN3 In order to understand the underlying pathophysiology of cutaneous or EDNRB can result in Waardenburg syndrome plus aganglionic mega­ disorders of hypopigmentation and hyperpigmentation, as well as colon (see Fig. 65.3). the process of normal physiologic pigment production, an apprecia­ Transcription factors represent another group of proteins that play an tion of the structure and function of the melanocyte is required. A essential role during embryogenesis. Because transcription factors can classic example of basic pathogenesis is type 1 oculocutaneous albi­ bind DNA and influence the activity of other genes, they are able to nism (OCA1), in which pigmentary dilution of the skin, hair, and regulate the complex interplay of various sets of genes that is required eyes is due to a reduction or absence of tyrosinase activity secondary for embryonic development. Several of the genes that, when mutated, to mutations in both copies of the tyrosinase gene (TYR). Within the give rise to Waardenburg syndrome encode transcription factors (e.g. realm of physiologic pigmentation, melanocytes in individuals with red PAX3, MITF, SOX10; see Table 66.4). Fig. 65.4 demonstrates some of hair often express variants of the melanocortin 1 receptor (MC1R)1. these interactions (e.g. PAX3 and SOX10 can control expression of As a consequence of the altered amino acid sequences of the variant MITF)8,9. MITF is sometimes referred to as the master regulator MC1Rs, their cell surface expression and interactions with melanocyte of melanocyte development and function given its modulation of mul­ stimulating hormone (MSH) can be affected, leading to an increase in tiple differentiation genes and its early up­regulation in neural crest the production of pheomelanin as opposed to eumelanin. Based upon cells that will eventually become melanocytes and emigrate from the population genetics, genes that are mutated in OCA (e.g. TYR, OCA2, dorsal neural tube. TYRP1, SLC45A2, SLC24A5) also influence normal pigment variation During embryogenesis, melanin­producing melanocytes are found (Table 65.1)2–6. diffusely throughout the dermis. They first appear in the head and neck The major sections in this chapter are: region at ~10 weeks of gestation. However, by the end of gestation, the origin and function of the melanocyte active dermal melanocytes have “disappeared”, except in three primary • the formation and function of the melanosome anatomic locations – the head and neck, the dorsal aspects of the distal • regulation of melanin biosynthesis. • extremities, and the presacral area10. Some of the dermal melanocytes have clearly migrated into the epidermis, but, given the absolute ORIGIN AND FUNCTION OF THE MELANOCYTE numbers of cells in the two compartments, apoptosis of pigment cells has also occurred. The three sites where active dermal melanocytes are The melanocyte is a neural crest­derived cell, and during embryogenesis still present at the time of birth coincide with the most common sites precursor cells (melanoblasts) migrate along a dorsolateral then ventral for dermal melanocytoses and dermal melanocytomas (blue nevi). pathway via the mesenchyme to reach the epidermis and hair follicles Hepatocyte growth factor may play a role in the survival and prolifera­ of the trunk (see Ch. 2). More recently, it was shown that cutaneous tion of these dermal melanocytes as well as somatic activating muta­ melanocytes can also arise from neural crest­derived Schwann cell tions in GNA11 and GNAQ, which encode G proteins and are found precursors that migrate along nerves to the skin via a distinct ventral in blue nevi (see Table 112.3). pathway7. Additional sites of melanocyte migration include the uveal As depicted in Fig. 65.1, melanocytes also migrate to the basal layer tract of the eye (choroid, ciliary body, and iris), the leptomeninges, and of the hair matrix and the outer root sheath of hair follicles. Cells that the inner ear (cochlea) (Fig. 65.1). Presumably, the death of melanocytes are actively producing melanin are easily recognized in the matrices of within the leptomeninges, inner ear, and skin is responsible for the pigmented anagen hairs, whereas melanocytes within the outer root aseptic meningitis, auditory symptoms, and areas of vitiligo, respec­ sheath are usually amelanotic and more difficult to identify11. It has tively, seen in patients with the Vogt–Koyanagi–Harada syndrome (see been hypothesized that there are two populations of melanocytes in the 1075 Ch. 66). skin, one in the interfollicular epidermis and the second in the hair non-print metadata ABSTRACT KEYWORDS: The major determinant of normal skin color is the activity of melano­ melanocyte, cytes, i.e. the quantity and quality of pigment production, not the melanosome, density of melanocytes. Melanocytes contain a unique intracytoplasmic tyrosinase, CHAPTER organelle, the melanosome, which is the site of melanin synthesis and eumelanin, deposition. Compared with lightly pigmented skin, darkly pigmented pheomelanin, 65 skin has melanosomes that contain more melanin and are larger; once melanocortin 1 receptor, transferred to keratinocytes, the melanosomes are singly dispersed and MC1R, degraded more slowly. Tyrosinase is the key enzyme in the melanin melanocyte stimulating hormone, biosynthetic pathway and the two major forms of melanin produced in MSH, melanocytes are brown–black eumelanin and yellow–red pheomelanin. pigmentation, The production of eumelanin versus pheomelanin is influenced by the agouti, binding of melanocyte stimulating hormone to the melanocortin 1 melanin biosynthetic pathway receptor. Melanocyte Biology 1075.e1 DISORDERS CHARACTERIZED BY DIFFUSE PIGMENTARY DILUTION IN WHICH THE GENETIC DEFECT IS KNOWN Disorder Gene Protein product Comments Oculocutaneous albinism (OCA) SECTION [~40% of patients have OCA1 and ~50% have OCA2] 10 OCA1A TYR Tyrosinase • Complete absence of tyrosinase activity and melanin production • Retention of misfolded tyrosinase protein within the ER • ers OCA1B TYR Tyrosinase Decreased tyrosinase activity; can produce pheomelanin • Variant with temperature-sensitive tyrosinase (normal activity at 35°C, but diminished at 37°C) • Additional variants: minimal pigment, platinum, yellow isord D OCA2 OCA2 P protein (OCA2 was • Melanosomal transmembrane protein that is also present in the ER previously known as P) • Possible functions include regulating organelle pH, facilitating vacuolar accumulation of glutathione, and processing/trafficking of tyrosinase OCA3 TYRP1 Tyrosinase-related protein 1* • TYRP1 stabilizes tyrosinase in mice and humans, and it can function as a DHICA oxidase igmentary • Both “mutant” TYRP1 and tyrosinase are retained in the ER and then degraded P • Rufous phenotype ≫ brown phenotype; latter seen in OCA2 OCA4 SLC45A2 Solute carrier family 45 • Variable phenotype, with hair ranging from white to yellow–brown; most common in Asians member 2 (previously
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