SKINIPEDIA - Skin Essentials: Melanocytes
Skin Essentials: Melanocytes by Jean L. Bolognia, MD, and Seth J. Orlow, MD, PhD
The pigment-producing cells of the skin are called melanocytes and their activity is the major determinant of the color of the hair and skin. Melanocytes originate in the neural crest and migrate to the basal layer of the epidermis and the hair matrices during embryogenesis. These neural crest-derived cells also populate the inner ear, uveal tract and leptomeninges. The failure of melanocytes to migrate to these locations explains the association of congenital white spotting of the skin (piebaldism) with heterochromia of the irises as well as congenital deafness in Waardenburg syndrome.
Within the epidermis, melanocytes reside in the basal layer in a ratio of about 10 keratinocytes to 1 melanocyte. However, each melanocyte via its dendrites supplies melanin to about 30 nearby keratinocytes.
A schematic diagram of the epidermis. The melanocyte resides in the basal layer and supplies melanin (packaged within melanosomes) to surrounding keratinocytes. Following exposure to ultraviolet light, there is an increase in the number of melanosomes, their melanin content and their transfer to keratinocytes.
Melanocytes contain a unique intracytoplasmic organelle, the melanosome. It is within the melanosome that the pigment known as melanin is produced and deposited.
A schematic diagram of the formation of a melanosome. The matrix proteins (MP) as well as tyrosinase (T), the major enzyme in the melanin biosynthetic pathway (see Figure 4), are synthesized on the rough endoplasmic reticulum (RER). Tyrosinase undergoes post translational modification in the form of glycosylation in the Golgi apparatus. Fusion of premelanosomes with coated vesicles containing tyrosinase result in the formation of the melanosome. As more melanin is deposited within the melanosome, it migrates into one of the dendrites of the melanocyte in anticipation of transfer to a neighboring keratinocyte.
Compartmentalization allows for efficiency and also protects the rest of the cell from the cytotoxic effects of melanin precursors; the latter are primarily phenols and quinones, compounds that alone or when oxidized have the ability to disrupt lipid membranes. Melanosomes, like lysosomes, have an acidic pH and the two organelles also have membrane proteins in common.
The melanin biosynthetic pathway is outlined in the graphic below. There are two major forms of melanin produced in the epidermis and hair follicles: eumelanin and pheomelanin. Eumelanin is brown to black in color whereas pheomelanin is yellow to red in color. The regulation of the production of eumelanin versus pheomelanin involves the interaction of the melanocortin 1 receptor (MC1R) on the surface of the melanocyte with either melanocyte stimulating hormone (MSH) or the agouti signaling protein (Figure 5). Binding of MSH to MC1R results in the formation of eumelanin, whereas the binding of the agouti protein to MC1R leads to the production of pheomelanin.
The melanin biosynthetic pathway. Tyrosinase regulates three of the steps, the conversions of tyrosine to DOPA, DOPA to dopaquinone, and DHI to indole-5,6-quinone. In one form of oculocutaneous albinism (OCA1), there are mutations in both copies of the tyrosinase gene, which result in an absence of or a significant decrease in tyrosinase activity. Abbreviations: Tyr = tyrosinase; TRP = tyrosinase-related protein; DHICA = 5,6-dihydroxyindole-2-carboxylic acid; and DHI = 5,6-dihydroxyindole. (Courtesy of Vincent Hearing, PhD.)
Recent studies have examined the nucleotide sequence of the MC1R receptor in various populations. (There are five forms of the MCR but only MC1R is found on melanocytes.) Variant sequences were found in more than 80 percent of individuals with red hair and/or fair skin that tanned poorly whereas these variant sequences were observed in less than 20 percent of persons with darkly pigmented hair and less than 4 percent of those with a good tanning response. Ultraviolet-induced tanning represents an increase in the content of eumelanin within the epidermis and its major purpose is increased photoprotection. The possibility exists that differences in the interactions between MSH or the agouti protein and the variant forms of MC1R could explain different pigmentation phenotypes in humans. Whether these variations in MC1R play a role in determining melanoma risk (beyond determining the degree of cutaneous pigment production) remains speculative.
Disorders of hypo- and hyperpigmentation can result from a change in the number of melanocytes or a decrease or increase in the activity of the melanocytes. Leukoderma in association with inflammatory disorders of the skin, e.g. atopic dermatitis and vitiligo, are two of the more common disorders of hypopigmentation. In biopsy specimens of well-developed lesions of vitiligo, there are few, if any, melanocytes remaining. Presumably, given the autoimmune nature of vitiligo, the melanocytes have been destroyed by autoreactive T lymphocytes. One of the most common disorders of hyperpigmentation is melasma (also known as mask of pregnancy) which is seen primarily, but not exclusively, in women and might or might not have its onset during pregnancy. Exposure to the sun plays a very important role in the induction and maintenance of these areas of hyperpigmentation on the face.
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