Melanocyte Biology




Abstract


The major determinant of normal skin color is the activity of melanocytes, i.e. the quantity and quality of pigment production, not the density of melanocytes. Melanocytes contain a unique intracytoplasmic organelle, the melanosome, which is the site of melanin synthesis and deposition. Compared with lightly pigmented skin, darkly pigmented skin has melanosomes that contain more melanin and are larger; once transferred to keratinocytes, the melanosomes are singly dispersed and degraded more slowly. Tyrosinase is the key enzyme in the melanin biosynthetic pathway and the two major forms of melanin produced in melanocytes are brown–black eumelanin and yellow–red pheomelanin. The production of eumelanin versus pheomelanin is influenced by the binding of melanocyte stimulating hormone to the melanocortin 1 receptor.




Keywords

melanocyte, melanosome, tyrosinase, eumelanin, pheomelanin, melanocortin 1 receptor, MC1R, melanocyte stimulating hormone, MSH, pigmentation, agouti, melanin biosynthetic pathway

 





Key features





  • The major determinant of normal skin color is the activity of melanocytes, i.e. the quantity and quality of pigment production, not the density of melanocytes



  • Melanocytes contain a unique intracytoplasmic organelle, the melanosome, which is the site of melanin synthesis and deposition



  • Compared with lightly pigmented skin, darkly pigmented skin has melanosomes that contain more melanin and are larger; once transferred to keratinocytes, the melanosomes are singly dispersed and degraded more slowly



  • Tyrosinase is the key enzyme in the melanin biosynthetic pathway



  • Two major forms of melanin are produced in melanocytes: brown–black eumelanin and yellow–red pheomelanin



  • The production of eumelanin versus pheomelanin is influenced by the binding of melanocyte stimulating hormone to the melanocortin 1 receptor





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 ) .



Table 65.1

Disorders characterized by diffuse pigmentary dilution in which the genetic defect is known.

See Chapter 66 for details of clinical findings. BLOC-1 promotes endosomal maturation by recruiting the Rab5 GTPase-activating protein Msb3; BLOC-2 targets recycling endosomal tubules to melanosomes for cargo delivery; BLOC-3 functions as a Rab32/38 guanine nucleotide exchange factor that is capable of activating small GTPases (activated Rab 32/38 is needed for transport of tyrosinase and TYRP1 to melanosomes). AP-3, adaptor protein complex 3; BLOC, b iogenesis of l ysosome-related o rganelles c omplex; DHICA, 5,6-dihydroxyindole-2-carboxylic acid; ER, endoplasmic reticulum; MATP, membrane associated transporter protein; TYRP, tyrosinase-related protein.





































































































































DISORDERS CHARACTERIZED BY DIFFUSE PIGMENTARY DILUTION IN WHICH THE GENETIC DEFECT IS KNOWN
Disorder Gene Protein product Comments
Oculocutaneous albinism (OCA)
[~40% of patients have OCA1 and ~50% have OCA2]
OCA1A TYR Tyrosinase


  • Complete absence of tyrosinase activity and melanin production



  • Retention of misfolded tyrosinase protein within the ER

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

OCA2 OCA2 P protein ( OCA2 was previously known as P )


  • Melanosomal transmembrane protein that is also present in the ER



  • 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



  • Both “mutant” TYRP1 and tyrosinase are retained in the ER and then degraded



  • Rufous phenotype ≫ brown phenotype; latter seen in OCA2

OCA4 SLC45A2 Solute carrier family 45 member 2 (previously known as MATP)


  • Variable phenotype, with hair ranging from white to yellow–brown; most common in Asians



  • Transmembrane transporter with a role in tyrosinase processing and intracellular trafficking of proteins to the melanosome

OCA5 Not known


  • Locus linked to 4q24

OCA6 SLC24A5 Solute carrier family 24 member 5


  • Cation exchanger that may be involved in ion transport in melanosomes

OCA7 C10orf11 Chromosome 10 open reading frame 11


  • Expressed in melanoblasts and melanocytes



  • Possible role in melanocyte differentiation

Hermansky–Pudlak syndrome (HPS)
HPS1 HPS1 HPS1 (BLOC-3 subunit 1)


  • Defective trafficking of organelle-specific proteins to melanosomes, lysosomes and cytoplasmic granules (including platelet dense granules and lytic granules in cytotoxic T lymphocytes)



  • Pulmonary fibrosis and granulomatous colitis



  • Component of BLOC-3 (see Fig. 65.8 )

HPS2 AP3B1 Adaptor related protein complex 3 β1 subunit


  • AP-3 recognizes sorting signals within cytosolic tails of cargo molecules and is involved in the trafficking of proteins from the trans-Golgi network to appropriate organelles (see Fig. 65.8 )



  • Pulmonary fibrosis (some patients)



  • Abnormal targeting of CD1 may play a role in associated immunodeficiency

HPS3 HPS3 HPS3 (BLOC-2 subunit 1)


  • Component of BLOC-2

HPS4 HPS4 HPS4 (BLOC-3 subunit 2)


  • Pulmonary fibrosis



  • Component of BLOC-3

HPS5 HPS5 HPS5 (BLOC-2 subunit 2)


  • Component of BLOC-2

HPS6 HPS6 HPS6 (BLOC-2 subunit 3)


  • Component of BLOC-2

HPS7 DTNBP1 Dystrobrevin binding protein 1


  • Component of BLOC-1

HPS8 BLOC1S3 BLOC1S3 (BLOC-1 subunit 3)


  • Component of BLOC-1

HPS9 BLOC1S6 BLOC1S6 (BLOC-1 subunit 6)


  • Component of BLOC-1

HPS10 AP3D1 Adaptor related protein complex 3 δ1 subunit


  • See AP-3 above



  • Neurologic impairment (e.g. seizures), immunodeficiency

Chédiak–Higashi syndrome
LYST Lysosomal trafficking regulator


  • Abnormal vesicle trafficking and fission/fusion of lysosome-related organelles result in giant organelles (e.g. melanosomes, neutrophil granules [lysosomes], platelet dense granules)

Griscelli syndrome
GS1 MYO5A Myosin Va (attaches melanosomes to actin filaments)


  • In all three forms, melanosomes are retained in the body of the melanocyte rather than trafficking to the tips of dendrites for transfer to keratinocytes (see Fig. 65.10 )



  • Silvery hair seen in all three forms



  • Myosin Va expressed in neurons (as well as melanocytes) and dysfunction leads to neurologic abnormalities

GS2 RAB27A RAB27A (melanosomal membrane GTPase that binds melanophilin)


  • GTPase also expressed in hematopoietic cells; defective release of granule contents from cytotoxic T cells leads to recurrent infections and hemophagocytic syndrome

GS3 MLPH Melanophilin (links myosin Va and RAB27A)


  • Melanophilin only expressed in melanocytes, so only pigmentary dilution in type 3

MYO5A Myosin Va F-exon deletion


  • F-exon only expressed in melanocytes


* Recognized by Mel-5 antibody.


Reflecting a founder effect, individuals of Puerto Rican origin have HPS1 and HPS3 (3 : 1 ratio); non-Puerto Ricans most commonly have HPS1, followed by HPS3 and HPS4 with ~70% of patients having one of these three types.



The major sections in this chapter are:




  • the origin and function of the melanocyte



  • the formation and function of the melanosome



  • 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 ).




Fig. 65.1


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 ).




Fig. 65.2


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.



Fig. 65.3


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.




Fig. 65.4


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.




Fig. 65.5


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.

Only gold members can continue reading. Log In or Register to continue

Tags:
Sep 15, 2019 | Posted by in Dermatology | Comments Off on Melanocyte Biology
Premium Wordpress Themes by UFO Themes