Introduction

In order to understand the underlying pathophysiology of cutaneous disorders of hypopigmentation and hyperpigmentation, as well as the process of normal physiologic pigment production, an appreciation of the structure and function of the melanocyte is required. A classic example of basic pathogenesis is type 1 oculocutaneous albinism (OCA1), in which pigmentary dilution of the skin, hair, and eyes is due to a reduction or absence of tyrosinase activity secondary to mutations in both copies of the tyrosinase gene ( TYR ). Within the realm of physiologic pigmentation, melanocytes in individuals with red hair often express variants of the melanocortin 1 receptor (MC1R) . As a consequence of the altered amino acid sequences of the variant MC1Rs, their cell surface expression and interactions with melanocyte stimulating hormone (MSH) can be affected, leading to an increase in the production of pheomelanin as opposed to eumelanin. Based upon population genetics, genes that are mutated in OCA (e.g. TYR , OCA2 , TYRP1 , SLC45A2 , SLC24A5 ) also influence normal pigment variation ( Table 65.1 ) .

The major sections in this chapter are:

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  the origin and function of the melanocyte

  
  
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  the formation and function of the melanosome

  
  
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  regulation of melanin biosynthesis.

Origin and Function of the Melanocyte

The melanocyte is a neural crest-derived cell, and during embryogenesis precursor cells (melanoblasts) migrate along a dorsolateral then ventral pathway via the mesenchyme to reach the epidermis and hair follicles of the trunk (see Ch. 2 ). More recently, it was shown that cutaneous melanocytes can also arise from neural crest-derived Schwann cell precursors that migrate along nerves to the skin via a distinct ventral pathway . Additional sites of melanocyte migration include the uveal tract of the eye (choroid, ciliary body, and iris), the leptomeninges, and the inner ear (cochlea) ( Fig. 65.1 ). Presumably, the death of melanocytes within the leptomeninges, inner ear, and skin is responsible for the aseptic meningitis, auditory symptoms, and areas of vitiligo, respectively, seen in patients with the Vogt–Koyanagi–Harada syndrome (see Ch. 66 ).

Migration of melanocytes from the neural crest.

Melanocytes migrate to the uveal tract of the eye (iris, ciliary body, and choroid), the leptomeninges, and the cochlea of the inner ear, as well as to the epidermis and hair follicle. Cutaneous melanocytes can also arise from Schwann cell precursors located along nerves in the skin, which also originate from the neural crest. The retina actually represents an outpouching of the neural tube.

In the inner ear, particularly in the stria vascularis, melanocytes are thought to play a role in the development of hearing. Aberrant migration or survival of melanocytes within the inner ear, the iris, and midportions of the forehead and extremities explains the presence of congenital deafness, heterochromia irides, and patches of leukoderma, respectively, in patients with Waardenburg syndrome, the classic neuro­cristopathy. Also, aberrant migration or survival of enteric ganglion cells, another neural crest-derived cell population, provides an explanation for the association of aganglionic megacolon (Hirschsprung disease) with Waardenburg syndrome or rarely piebaldism.

The survival and migration of neural crest-derived cells during embryogenesis depends upon interactions between specific receptors on their cell surface and extracellular ligands. For example, KIT ligand (also known as steel factor or stem cell growth factor) binds to the transmembrane KIT receptor on melanocytes and melanocyte precursors (melanoblasts) ( Figs 65.2 & 65.3 ); melanoblasts require expression of the KIT receptor in order to maintain their normal chemotactic 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 migrate by endothelin-3 (ET3 [EDN3]), which is produced by the ectoderm and dermamyotome. Mutations in one or both copies of EDN3 or EDNRB can result in Waardenburg syndrome plus aganglionic megacolon (see Fig. 65.3 ).

Activation of the KIT receptor on melanocytes.

Because the KIT receptor is a tyrosine kinase receptor, it has the ability to phosphorylate the tyrosine residues of other proteins as well as itself, i.e. autophosphorylation. Heterozygous germline mutations in KIT that prevent the activation of the KIT receptor by KIT ligand, also referred to as steel factor, lead to piebaldism, whereas somatic activating mutations in KIT are seen in patients with mastocytosis as well as melanomas arising in acral sites, mucosae, and chronically photodamaged skin (see Fig 118.2 , Fig 113.1 ). A form of familial progressive hyperpigmentation with or without hypopigmentation can result from heterozygous gain-of-function germline mutations in the gene that encodes KIT ligand . P, phosphorylation; Tyr, tyrosine.

Receptor–ligand interactions in precursors of melanocytes.

In the developing embryo, melanoblasts expressing endothelin receptor type B (EDNRB) are stimulated to migrate by endothelin-3 (ET3) which is produced by the ectoderm and dermamyotome. Melanoblasts also require expression of the KIT receptor to maintain their normal chemotactic migration directed by production of KIT ligand/steel factor by the dermamyotome.

Transcription factors represent another group of proteins that play an essential role during embryogenesis. Because transcription factors can bind DNA and influence the activity of other genes, they are able to regulate the complex interplay of various sets of genes that is required for embryonic development. Several of the genes that, when mutated, give rise to Waardenburg syndrome encode transcription factors (e.g. PAX3, MITF, SOX10 ; see Table 66.4 ). Fig. 65.4 demonstrates some of these interactions (e.g. PAX3 and SOX10 can control expression of MITF) . MITF is sometimes referred to as the master regulator of melanocyte development and function given its modulation of multiple differentiation genes and its early up-regulation in neural crest cells that will eventually become melanocytes and emigrate from the dorsal neural tube.

Signal transduction pathways and transcription factors that contribute to melanocyte differentiation.

MITF expression is activated early on during the transition from pluripotent neural crest cells to melanoblasts and is required for melanoblast survival ; mutations in MITF lead to Waardenburg syndrome, a classic neurocristopathy. MITF also regulates the expression of multiple pigment genes including those that encode tyrosinase, TYRP1, TYRP2, PMEL/PMEL17/gp100, and MART-1/Melan-A. Additional transcriptional targets are CDK2 , CDKN2A , and BCL-2 (whose protein product is an inhibitor of apoptosis) . Small molecule inhibitors of SIK (salt-inducible kinase) can upregulate MITF, and application of these inhibitors to normal human skin led to an increase in pigmentation . In mice, Wnt signaling in melanocyte stem cells is critical for hair pigmentation . Details of how activation of G-protein-coupled receptors leads to an increase in intracellular cAMP is shown in Fig. 65.15 . Of note, EDNRB interacts with the G proteins GNAQ and GNA11, and activating mutations in the genes that encode these latter two proteins can lead to blue nevi and phakomatosis pigmentovascularis. cAMP, cyclic adenosine monophosphate; CREB, cAMP response-element binding protein; ET3, endothelin-3; EDNRB, endothelin receptor type B; LEF1, lymphoid enhancer binding factor 1; MC1R, melanocortin 1 receptor; MITF, microphthalmia-associated transcription factor; MSH, melanoctye stimulating hormone; P, phosphorylation; PKA, protein kinase A; SOX10, SRY-box containing gene 10.

During embryogenesis, melanin-producing melanocytes are found diffusely throughout the dermis. They first appear in the head and neck region at ~10 weeks of gestation. However, by the end of gestation, active dermal melanocytes have “disappeared”, except in three primary anatomic locations – the head and neck, the dorsal aspects of the distal extremities, and the presacral area . Some of the dermal melanocytes have clearly migrated into the epidermis, but, given the absolute numbers of cells in the two compartments, apoptosis of pigment cells has also occurred. The three sites where active dermal melanocytes are still present at the time of birth coincide with the most common sites for dermal melanocytoses and dermal melanocytomas (blue nevi). Hepatocyte growth factor may play a role in the survival and proliferation of these dermal melanocytes as well as somatic activating mutations in GNA11 and GNAQ , which encode G proteins and are found in blue nevi (see Table 112.3 ).

As depicted in Fig. 65.1 , melanocytes also migrate to the basal layer of the hair matrix and the outer root sheath of hair follicles. Cells that are actively producing melanin are easily recognized in the matrices of pigmented anagen hairs, whereas melanocytes within the outer root sheath are usually amelanotic and more difficult to identify . It has been hypothesized that there are two populations of melanocytes in the skin, one in the interfollicular epidermis and the second in the hair follicle . Based upon antigen expression and clinical observations, it is the former that is more sensitive to the destructive forces of vitiligo. As a result, repigmentation of patches of vitiligo in which the hairs are still pigmented relies upon activation and subsequent upward migration of the melanocytes present in the outer root sheath . Of note, melanocyte stem cells have been identified within the lower portion of the hair follicle bulge, i.e. the lowermost permanent portion of the hair follicle (see Fig. 2.6 ). In addition, KROX20+ cells, which give rise to the hair shaft, have recently been identified within the hair bulb. These hair progenitor cells produce stem cell factor (SCF) which was shown to be essential for hair pigmentation, i.e., mouse hairs turn white when the SCF gene was deleted .

By immunohistochemical staining, melanocytes are identified within the fetal epidermis as early as 50 days of gestation . Melanin-containing melanosomes are recognizable by electron microscopy during the fourth month of gestation. Except in benign and malignant neoplasms, melanocytes reside within the basal layer of the epidermis, a location they maintain throughout life ( Fig. 65.5 ). Although the cell body of the melanocyte sits on a specialized region of basal lamina, its dendrites come into contact with keratinocytes as far away as the mid stratum spinosum. This association of a melanocyte with ~30–40 surrounding keratinocytes to which it transfers melanosomes has been called the epidermal melanin unit . However, melanocytes fail to form desmosomal connections with neighboring keratinocytes; their interactions with keratinocytes are via cadherins.

A melanocyte residing in the basal layer of the epidermis.

In normal skin, approximately every tenth cell in the basal layer is a melanocyte. Melanosomes are transferred from the dendrites of the melanocyte into neighboring keratinocytes of the epidermis, hair matrices and mucous membranes; no transfer occurs in the pigment epithelium of the retina. The epidermal melanin unit refers to the association of a melanocyte with ~30–40 surrounding keratinocytes to which it transfers melanosomes.

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