Draft:Original research/Melanocytes

Melanocytes are ink cells, from the Greek μέλανo-ink, or black ink and χυτός-cast, for cell.

Genetics
Def. a "branch of biology that deals with the transmission and variation of inherited characteristics, in particular chromosomes and DNA" is called genetics.

In humans, a melanogenic enzyme, tyrosinase, is produced by the gene, Gene ID: 7299. Actually, this gene produces a precursor to the enzyme. The precursor is activated once inside a closed melanosome.

"The enzyme [EC 1.14.18.1] encoded by this gene [GeneID: 7299] catalyzes the first 2 steps, and at least 1 subsequent step, in the conversion of tyrosine to melanin. The enzyme has both tyrosine hydroxylase and dopa oxidase catalytic activities, and requires copper for function."

“Understanding how [GeneID: 3662] IRF4 influences hair graying could help the development of new cosmetic applications that change the appearance of hair as it grows in the follicle by slowing or blocking the graying of hair.”

Gene ID: 4157 is MC1R melanocortin 1 receptor. "This intronless gene encodes the receptor protein for melanocyte-stimulating hormone (MSH). The encoded protein, a seven pass transmembrane G protein coupled receptor, controls melanogenesis. Two types of melanin exist: red pheomelanin and black eumelanin. Gene mutations that lead to a loss in function are associated with increased pheomelanin production, which leads to lighter skin and hair color. Eumelanin is photoprotective but pheomelanin may contribute to UV-induced skin damage by generating free radicals upon UV radiation. Binding of MSH to its receptor activates the receptor and stimulates eumelanin synthesis. This receptor is a major determining factor in sun sensitivity and is a genetic risk factor for melanoma and non-melanoma skin cancer. Over 30 variant alleles have been identified which correlate with skin and hair color, providing evidence that this gene is an important component in determining normal human pigment variation."

Gene ID: 4158 is MC2R melanocortin 2 receptor. "MC2R encodes one member of the five-member G-protein associated melanocortin receptor family. Melanocortins (melanocyte-stimulating hormones and adrenocorticotropic hormone) are peptides derived from pro-opiomelanocortin (POMC). MC2R is selectively activated by adrenocorticotropic hormone, whereas the other four melanocortin receptors recognize a variety of melanocortin ligands. Mutations in MC2R can result in familial glucocorticoid deficiency. Alternate transcript variants have been found for this gene."


 * 1) NP_000520.1 adrenocorticotropic hormone receptor variant 1.
 * 2) NP_001278840.1 adrenocorticotropic hormone receptor variant 2.
 * 3) XP_016881270.1 adrenocorticotropic hormone receptor isoform X1.

Gene ID: 4159 is MC3R melanocortin 3 receptor. "This gene encodes a G-protein-coupled receptor for melanocyte-stimulating hormone and adrenocorticotropic hormone that is expressed in tissues other than the adrenal cortex and melanocytes. This gene maps to the same region as the locus for benign neonatal epilepsy. Mice deficient for this gene have increased fat mass despite decreased food intake, suggesting a role for this gene product in the regulation of energy homeostasis. Mutations in this gene are associated with a susceptibility to obesity in humans."

Gene ID: 4160 is MC4R melanocortin 4 receptor. "The protein encoded by this gene is a membrane-bound receptor and member of the melanocortin receptor family. The encoded protein interacts with adrenocorticotropic and MSH hormones and is mediated by G proteins. This is an intronless gene. Defects in this gene are a cause of autosomal dominant obesity."

Gene ID: 4161 is MC5R melanocortin 5 receptor. "This gene encodes a member of the seven-pass transmembrane G protein-coupled melanocortin receptor protein family that stimulate cAMP signal transduction. The encoded protein is a receptor for melanocyte-stimulating hormone and adrenocorticotropic hormone and is suggested to play a role in sebum generation."

Gene ID: 4286 is MITF melanocyte inducing transcription factor. "The protein encoded by this gene is a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. The encoded protein regulates melanocyte development and is responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome."


 * 1) NP_937802.1 microphthalmia-associated transcription factor isoform 1.
 * 2) NP_937820.1 microphthalmia-associated transcription factor isoform 2.
 * 3) NP_006713.1 microphthalmia-associated transcription factor isoform 3.
 * 4) NP_000239.1 microphthalmia-associated transcription factor isoform 4.
 * 5) NP_937801.1 microphthalmia-associated transcription factor isoform 5.
 * 6) NP_937821.2 microphthalmia-associated transcription factor isoform 6.
 * 7) NP_001171896.1 microphthalmia-associated transcription factor isoform 7 (variant 7).
 * 8) NP_001341537.1 microphthalmia-associated transcription factor isoform 7 (variant 13).
 * 9) NP_001171897.1 microphthalmia-associated transcription factor isoform 8.
 * 10) NP_001341533.1 microphthalmia-associated transcription factor isoform 9.
 * 11) NP_001341534.1 microphthalmia-associated transcription factor isoform 10.
 * 12) NP_001341535.1 microphthalmia-associated transcription factor isoform 11.
 * 13) NP_001341536.1 microphthalmia-associated transcription factor isoform 12.

Gene ID: 4948 is

Gene ID: 5443 is POMC, proopiomelanocortin, melanocyte-stimulating hormone (MSH).

Gene ID: 6490 is

Gene ID: 7299 is

Gene ID: 7306 is

Gene ID: 79648 is MCPH1 microcephalin 1. "This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described."


 * 1) NP_078872.3 microcephalin isoform 1.

Gene ID: 83938 is

Gene ID: 107988030 is

Cytology
Def. "the study of cells" is called cytology.

(A) During embryogenesis, melanoblasts emerge in the neural crest at embryonic day (E) 9.5–10.5. These earliest stages of melanoblasts are characterized by the expression of Dct, Kit, Mitf, Pax3, Sox10, and Si. Once arising from the neural crest, melanoblasts migrate in the developing dermis toward the ventral midline. Subsequently, at E12.5–13.5, they enter the epidermis where they actively migrate and proliferate to distribute around the entire body. In addition to the pre-migratory melanoblast markers, these migratory melanoblasts express several melanosomal proteins including Tyr and Tyrp1. Upon initiation of hair follicle morphogenesis, the melanoblasts enter the newly developing follicle and are segregated into two populations: one locates in the hair matrix where melanoblasts are differentiated into mature melanocytes; and the other colonizes at the putative bulge region, where melanoblasts are restricted in a resting status to become melanocyte stem cells. Melanocytes in the hair matrix express Oa1 and Mcr1 in addition to the migratory melanoblast markers, whereas in the bulge melanoblasts, expression of several melanoblast markers including Kit, Mitf, Pax3, Sox10, Tyr, and Tyrp1 are gradually downregulated. (B) Melanoblast localization occurs during hair follicle morphogenesis. Skin fragments from Dct-LacZ transgenic mice were whole-mount stained with LacZ to visualize melanoblasts in the developing hair follicle. Melanoblasts colonize at the putative bulge region at stage 5–6 of hair follicle morphogenesis, suggesting stem cell specification would take place from stage 5–6 of hair follicle morphogenesis onward.

Neural crest cells
"Melanocytes differentiate from the neural crest (NC), which is a transient population of cells that delaminates from the neural tube and migrates extensively throughout the embryo during vertebrate development. Melanoblast specification from NC precursors is a progressive process during which initially pluripotent cells become restricted to the melanogenic lineage and adopt the gene expression profile and morphology of melanocytes. This specification process is governed primarily by Wnt and BMP signaling molecules, although other signaling pathways, such as those activated by Kit and Endothelin 3, can also stimulate melanogenesis. The transcriptional repressor FoxD3 occupies a central role in melanocyte fate determination by repressing melanogenesis in premigratory NC cells and in other NC lineages." On the right are images of mice wherein defects in melanocyte development cause white spotting, while the stem cell defect results in hair graying: (A) A Ednrbs-l/Ednrbs-l mouse demonstrating extensive piebald spotting. (B) A KitW-2J/+ mouse demonstrating a white head blaze, and small dorsal spot on the back. (C) A Sox10Lacz/+ mouse exhibiting the characteristic white belly spot. (D) A Mitfvit/vit mouse (upper) exhibits gradual hair graying. A lower mouse is an age-matched control.

Melanoblasts
Def. a "precursor cell of a melanocyte" is called a melanoblast.

The "genetic makeup of cells defines the limits and the potentialities of their development, and [...], the diverse cellular environments of the embryo elicit the specific developmental responses in cells which lead to their maturation into the wide variety of cell types that characterizes the adult."

Within "any single animal at least four distinct factors are important in melanoblast differentiation: (1) the genotype of the melanoblast, (2) the genotype of the environmental cells, (3) the environmental history of the melanoblast, and (4) the differentiated characteristics of the environmental cells-that	is, whether the cells are epidermal cells, dermal cells, harderian gland cells, etc. [These] four factors have been considered in the differentiation of the melanocytes in house mice (Mus musculus) of 50 different genotypes involving genes at 15 distinct loci."

(A) is a schematic illustration of the hair follicle. The hair follicle is divided into two portions: two-thirds of lower hair follicle (transit portion) that completely reforms itself over the hair cycle; and the upper permanent portion of the follicle that is maintained throughout hair cycling. Melanocyte stem cells reside in the lower permanent portion including the bulge region, while differentiated melanocytes are localized in the hair matrix. (B) Whole mount staining of the Dct-LaZ hair follilce. Using Dct-LaZ transgenic mice, melanocyte stem cells can be located at the lower permanet portion of the hair follicle, which is anatomically segregated from differentiated melanocytes in the hair bulb.

Theoretical melanocytes
A melanocyte is a cell containing the pigment melanin, which has several forms. A cell which yields or produces melanin, or one of its forms, may be called a melanoparagocyte, where parag- or parago- is from παραγ-yield or produce, or παραγο-producing.

Def. "a cell in the skin that produces the pigment melanin" is called a melanocyte.

As shown in the image on the right, skin melanocytes are located in basal cell layer.

Melanocytogenesis
Def. "the differentiation of melanoblasts into melanocytes" is called melanocytogenesis.

Melanogenesis
Def. the "production of melanin in human skin" is called melanogenesis.

In the image on the right, melanocyte distribution has been genetically controlled to produce a zebra-fish.

Transfection "of [the silver locus gene] into fibroblasts is associated with the expression of stablin, a melanogenic inhibitor that regulates further metabolism of intermediates [such as DHI and DHICA] in the [melanin] pathway (Chakraborty et al. 1992)."

"The initial rate-limiting reaction, tyrosine hydroxylase (1), is specifically catalyzed only by tyrosinase; tyrosinase can also catalyze the second reaction, DOPA oxidation (2). If glutathione and/or cysteine is available, DOPAquinone will stoichiometrically be diverted to the production of cysteinylDOPAs (3); intracellular levels of these sulfhydryls are regulated by γ-glutamyl transpeptidase and glutathione reductase, among others. In their absence, DOPAquinone will quickly cyclize to produce leukoDOPAchrome, which will then rearrange to form the more stable intermediate termed "DOPAchrome." In the presence of DOPAchrome tautomerase (TRP-2) and/or divalent metal cations, DOPAchrome will be diverted to DHICA (4), whereas, in the absence of those factors, DOPAchrome will decarboxylate to produce DHI. DHI is then oxidized to indole-5,6-quinone (5), a reaction catalyzed by tyrosinase or peroxidase, thence incorporated within eu-melanins. DHICA is presumed to be similarly oxidized to a carboxylated indole-quinone (7); preliminary findings suggest that this catalytic activity might be performed by TRP-1. There are many inhibitory factors (6) of the reactions leading to melanin production, and it is generally accepted that there are many other undiscovered melanogenic factors that can influence other parts of this reaction sequence, most notably those on the phaeomelanic side of the pathway (8). Although genetically inbred mice produce eu-melanin or phaeo-melanin, in humans there is usually a variable mixture of the two types, which are referred to as "mixed melanins.""

Melanins
Def. a "dark brown pigment related to melanin" is called eumelanin.

Def. any "of a group of naturally occurring dark pigments, especially the pigment found in skin, hair, fur, and feathers" is called a melanin.

Def. a "dark pigment present in parts of the brain" is called neuromelanin.

Def. any "of a class of pigments related to melanin and found in human hair" is called trichochrome.

In the facial skin (left panel in the image on the right), neural crest-derived structures (shown in blue) harbor NCSCs located in the bulge, dermal sheath (DS), and dermal papilla (DP). NCSCs associated with the glial lineage are associated with nerve endings. Melanocyte stem cells in the bulge (MSCs), melanoblasts (Mb), and melanocytes (M) are as well of neural crest origin. In the facial skin, skin-derived precursors (SKPs) located in the dermal papilla originate from the neural crest. Moreover, note that other structures such as the capsula and ringwulst (not labeled in the scheme) contain neural crest-derived cells with sphere-forming potential.In the trunk skin (right panel), NCSCs are found both in the bulge containing MSCs and associated with nerve endings. Melanoblasts (Mb) and melanocytes (M) are of neural crest origin as well. Note that dermal papilla (DP) does not derive from the neural crest in the trunk skin. SKPs (shown in green) reside in the DP and can be isolated by means of their GFP expression in Sox2-GFP mice.

Pheomelanins
Def. a "brown pigment produced by melanocytes" is called pheomelanin.

Amelanism
Amelanistic animals such as the Burmese python imaged on the right owes its yellow color to unaffected carotenoid pigments.

A Zebrafish Pigment Mutant in the image on the left called bleached blond was produced by insertional mutagenesis. The embryos in the picture are four days old. At the top is a wild-type embryo, below is the mutant. The mutant lacks black pigment in the melanocytes because it fails to synthesise melanin properly. Yet the insertional mutagenesis has left a few melanin producing melanocytes.

Aeumelanism
Without melanocortin 1 receptor to signal eumelanin production in melanocytes, or high activity of the MC1R-antagonist, Agouti signalling peptide, an animal such as the Labrador retriever in the image on the right has a yellow coat, but his eyes and skin are normal.

Apheomelanin
In the image on the right, the bay horse, left, has both eumelanin and phaeomelanin in her coat, where the agouti signaling peptide suppresses black color except to the "points" - the mane, tail, ear tips, and legs. The horse at right lacks phaeomelanin in her coat, and has a uniformly black or aphaeomelanistic coat.

A chestnut horse such as in the image on the left has lost all types of black melanin.

Melanosomes
Def. any "organelle that contains melanin" is called a melanosome.

In the image on the right, ELKS interacts with RAB6 to direct cargo vesicles along microtubules to melanosomes.

Pseudopods
The movie on the right of a melanocyte in vitro and in liquido shows a melanocyte sending out pseudopods and dendrites to yield melanosomes for nearby cells.

Keratinocytes
On the right is a simplified schematic showing of the key molecules and signaling pathways implicated in melanocyte-keratinocyte interactions.

In the melanocyte lineage, a series of transcription factors, including PAX3, SOX10, CREB1, LEF1, and MITF play crucial roles in the regulation of melanocyte proliferation, differentiation, and survival. Expression of the melanocyte master regulatory gene MITF is regulated by synergistic action of PAX3, SOX10, LEF1, and CREB1 on its promoter/enhancer. MITF activates its own promoter by a positive feedback loop. Once translated, MITF protein is phosphorylated by the Erk kinase downstream during activation of c-Kit signaling pathway. Phosphorylation of MITF results in stabilization of the MITF-p300 transactivation complex, and thereby upregulating its transcriptional activity to stimulate expression of the target genes including DCT, Typ, and Tyrp1. c-Kit signaling also stimulates the expression of Bcl2 to mediate melanocyte survival. Activation of melanocortin signaling pathway increases cytoplasmic cAMP concentration, which results in activation of CREB1. This activated CREB1 directly binds the cAMP-responsive elements present on the promoter regions of MITF and various melanosomal genes, and stimulates their gene expressions. Wnt signaling is required for melanocyte development. Activation of Wnt signaling results in the stabilization of β-catenin/Lef complex, which leads in transactivation of downstream target genes such as MITF to promote melanocyte-fate specification and melanocyte differentiation. In contrast, keratinocyte expression of TGF-β plays a role in suppressing melanogenesis. Activation of TGF-β signaling results in the repression of Pax3 through phosphorylated Smads, which leads to MITF repression to block melanocyte activation. Activation of Notch signaling is essential for the survival of melanoblasts, while underlying molecular mechanism is unclear. pSmad, phosphorylated Smads; Fzd, Frizzeled; cAMP, adenosine 3′:5′-cyclic monophosphate; CREB, cAMP responsive element binding protein, Pkc protein kinase C; Erk, extracellular signal-regulated kinase/mitogen-activated protein kinase, and pMitf, phosphorylated MITF. Signaling molecules and transcription factors whose physiological roles in melanocytes are evidenced by genetic mutant animals are shown in red.

Graying
On the right is a set of images showing a case of apoptosis, or cell death, of melonocytes, making the cat almost completely white over the period of 6 years; note the slow pigment change around the nose and eyes.

On the left are a set of images: both Notch1−/+ (A) and Notch2−/+ (B) mice show no obvious defect in hair pigmentation, while combinatory attenuation of Notch and c-Kit signaling enhances the spotting phenotype of W v/+ mice, suggesting a link between Notch signaling and c-Kit signaling, (C), Notch1−/+; Wv/+; (D), Notch2−/+; Wv/+; (E), Notch1−/+; Notch2−/+; Wv/+.

"The average human scalp has 100,000 hair follicles, and a wide range of hair colours can be found across the human population. Hair colour is determined by cells called melanocytes, which produce different combinations of light-absorbing melanin pigments2. Melanocytes are derived from melanocyte stem cells (MeSCs), which are located in a part of the hair follicle called the bulge3. The normal hair cycle is divided into three stages: hair-follicle regeneration (anagen), degeneration (catagen) and rest (telogen). Melanocyte production begins early in the anagen phase [...]. As people age, the pool of MeSCs is gradually depleted — and so pigmented hair becomes ‘salt and pepper’ coloured, and then turns to grey and finally to white after a complete loss of pigment in all hair follicles4."

"Melanocyte stem cells (MeSCs) are located in the bulge of the hair follicle, which is innervated by neurons of the sympathetic nervous system that release the neurotransmitter molecule noradrenaline. The follicle cycles through three phases: regeneration (anagen), degeneration (catagen) and rest (telogen). Under normal conditions, MeSCs migrate away from the bulge [toward the epidermis] and differentiate into melanocytes during anagen. Melanocytes synthesize pigments that add colour to the regenerating hair. During catagen and telogen, they begin to die and migrate out of the niche [...]. However, plentiful MeSCs remain to replace the melanocytes in the next anagen phase. Zhang et al.1 show that stressful stimuli activate the sympathetic nervous system, increasing noradrenaline release in hair follicles. Noradrenaline causes complete conversion of MeSCs into melanocytes, which migrate out of the niche in catagen and telogen. The hair follicle is depleted of MeSCs that would have differentiated to replace these melanocytes. Without any pigment cells to colour the hair in the next anagen phase, it begins to look grey or white."

"MeSCs express β2-adrenergic receptors, which respond to noradrenaline — a neurotransmitter molecule involved in the ‘fight or flight’ response to stress. Loss of this receptor specifically in MeSCs completely blocked stress-induced greying."

Removing adrenal glands "the main source of circulating noradrenaline [...] did not prevent greying in response to stress in the mice. Another source of noradrenaline is the sympathetic nervous system (SNS), which is highly active in response to stress, and which drives the fight-or-flight response. [Bulge] regions are highly innervated by sympathetic neurons, and that ablating the SNS using a neurotoxin molecule, or blocking the release of noradrenaline from sympathetic neurons, prevented stress-induced greying."

With "mice in which sympathetic neurons could be acutely activated [...] overactivation of the SNS in these mice caused greying in the absence of stress. [These] results indicate that noradrenaline released from active sympathetic neurons triggers MeSC depletion [The] propensity of an area to turn grey correlates with its level of sympathetic innervation.

"MeSC proliferation and differentiation increase markedly under extreme stress or exposure to a high level of noradrenaline. This results in mass migration of melanocytes away from the bulge, and leaves no remaining stem cells."

"Perhaps, in the absence of sympathetic signals, MeSCs have the capacity for unlimited replenishment, pointing to a way to delay age-related greying."

Adult "male silverback mountain gorillas (Gorilla beringei beringei), which get grey hair on their backs after reaching full maturity, can go on to lead a gorilla troop16. Perhaps an animal that has endured enough stress to ‘earn’ grey hair has a higher place in the social order than would ordinarily be conferred by that individual’s age."

Chromatophores
Def. a "pigment-bearing cell or structure found in certain fish, reptiles, cephalopods, and other animals" is called a chromatophore.

Def. a "chromatophore that appears red under white light" is called an erythrophore.

Def. a "cell, found in some animals, that is filled with iridescent crystals of guanine" is called an iridocyte.

Def. any "chromatophore that shows white in reflected light" is called a leucophore.

Def. a "xanthochrome-containing chromatophore, frequently a lipophore" is called a xanthophore.

Def. a "lipochrome-containing chromatophore" is called a lipophore.

The amelanistic ("lutino") cockatiels in the image on the right retain their carotenoid-based red and pteridine yellow pigments.

Melanophores
Def. a "cell containing melanin or other black pigment, such as are found in fish, amphibians, and reptiles" is called a melanophore.

Multi-nucleate melanocytes
In the movie on the right multi-nucleate melanocytes in green are shown dividing apparently to produce single-nucleate melanocytes.

Visuals
The image at the right shows a melanophore containing melanosomes (A), dispersed melanophores (B), fluorescent undispersed melanophores (C), and fluorescent dispersed melanophores (D).

The melanosomes have been dispersed out into the cells dendrites.

As an example, the image at the left shows a male bitterling Rhodeus amarus where the dark appearance of its dorsal surface is produced by a dispersal of melanosomes to simulate the dark bottom of the fish tank.

Locations
"Melanin in melanocytes located in meninges and along cerebral capillaries occurred in abundance in C57 black mice and to a lesser extent in pigmented rats. Meningeal melanin bound cupric and ferrous ions, reduced ferricyanide, and appeared golden-brown in the bright field, light scattering in the dark field, and absorbant in the ultraviolet."

There "seem to be three subpopulations of neural crest-derived melanocytes in the body that can be functionally and morphologically distinguished: the cutaneous melanocytes, which continuously synthesize small melanosomes to be transferred to keratinocytes; the uveal melanocytes, which synthesize larger melanosomes for only a short while to be retained by this melanogenically dormant cell; and the hair melanocyte, which intermittently produces melanin either in a cyclic manner or as a periodic supply from a stem population."

As shown in the images on the right, melanocytes or their absence produce white areas on horses hides.

Cutaneous melanocytes
Skin sections from Dct-LacZ transgenic mice were stained [in the images on the left] with antibody against either phosphorylated Smad1/5/8, Lef1, c-Kit, or phosphorylated MEK1/2 (shown in green). Melanoblasts/melanocytes in the hair bulb or the bulge region are visualized by anti-LacZ antibody (shown in red). Melanocytes in the hair bulb are positively stained with these antibodies, indicating that BMP, c-Kit, and Wnt signaling pathways are activated in these cells. In contrast, none of these markers are detectable in the bulge melanoblasts, suggesting that these signaling pathways may not be implicated in melanocyte stem cell regulation.

Corneal melanocytes
Limbal epithelial stem cells shown in the diagram on the right reside in the basal layer of the epithelium (Ep), which undulates at the limbus. Daughter transient amplifying cells (TACs) divide and migrate towards the central cornea (arrowed) to replenish the epithelium, which rests on Bowman's layer (BL). The stroma (St) of the limbal epithelial stem cell niche is populated with fibroblasts and melanocytes and also has a blood supply.

Hyperpigmentation
Def. the "darkening of an area of skin or nails, caused by increased melanin" is called hyperpigmentation.

Def. the "morbid deposition of black matter, often of a malignant character, causing pigmented tumours" is called melanosis.

Cancers
Influence of pigmentation on skin cancer risk: fair-skinned individuals with low levels of melanin in the epidermis display a UV sensitive phenotype, tending to burn rather than tan, after UV exposure. Recent data suggest that mutations that contribute to fair complexion and tanning impairment, specifically signaling defects in the melanocortin 1 receptor (MC1R), may also be associated with less efficient DNA repair in melanocytes. MC1R-defective individuals not only suffer higher realized doses of UV radiation because their skin is less able to block UV photons, but they may also accumulate more mutations from UV exposure because of defective DNA repair.

Melanomas
Def. a "dark-pigmented, usually malignant tumor arising from a melanocyte and occurring most commonly in the skin" is called a melanoma.

In the image in the center, A: Phenotypically derived gene cluster associated with Melanoma. MITF is the only gene in the cluster not associated with Melanoma. B: The Melanogenesis pathway (KEGG: hsa:04916) with genes MITF, TYR and ASP (ASIP in A) colored in red. C: Neighborhood of MITF gene in network ALL.

Neurofibromatosis
Lisch nodules are numerous nodules of dendritic melanocytes in aggregates within the iris as shown in the image on the right. They are brown-yellow, round shape, raised papules as seen with slit lamp examination in the iris of patients with Neurofibromatosis type 1(>90% of cases) together with scattered café au lait pigmented skin lesions and multiple neurifibromas (superficial or deep) in skin or other organs. Similar nodules are also found in Watson syndrome which is in addition characterized by macrocephaly, pulmonary stenosis, short status and low intelligence. No treatment is required but a close follow-up of main diseases is mandatory for avoiding any serious complications.

Vogt–Koyanagi–Harada syndrome
The diagnostic clue in this patient imaged on the right is the telltale loss of hair coloring in the left eyebrow and eyelashes (poliosis) with contiguous vitiligo. Additional features of this syndrome—all of which this patient had—include panuveitis, retinal detachment, pinpoint retinal leaks on fluorescein angiography, and evidence of auditory and central nervous system dysfunction, including aseptic meningitis. Decreased visual acuity is the rule. The cause is uncertain, but immune-mediated damage of melanocyte-containing tissue seems likely. Long-term corticosteroid therapy usually halts further ocular damage and often improves vision.

Hypotheses

 * 1) Each location of a melanocyte has a genetically unique melanocyte.
 * 2) Melanoblasts can be signaled to divide with daughter cells migrating to locations formerly occupied by melaoncytes, e.g. dermal matrix.