20 - Pigmentation and Melanocyte Biology Flashcards by dvojnd rivera

Specialized cells of the epidermis and hair follicle whose primary function is to synthesize and transfer melanjn to adjacent keratinocytes

Melanocytes

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Melanin synthesis occurs in a specialized organelle

Melanosome

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Y/N: Melanocyte numbers are different in individuals of different racial backgrounds

No - similar

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Location of melanocytes

Basal layer of the epidermis
Hair bulb
Outer root sheath

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Melanocytes contain (round/oval) nuclei slightly (larger/smaller) than that of surrounding keratinocytes

Oval

Smaller

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Melanocytes are present at about ______ the number of keratinocytes

1/10

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Silver stains that rely on the ability of melanin to become impregnated with silver

Fontana-Mason stain

Warthin-Starry stain

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Y/N: Silver stains react with melanocytes from eumelanotic, but not pheomelanotic skin tissue

Yes

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Immunohistologic identification of melanocytes using antibodies directed against

Tyrosinase
MITF
Melan-A/Mart1

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Although less specific for melanocyte lineage, antibodies directed against _____ protein have long been used with great sensitivity to detect melanocytes and melanoma

S100

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Immunostaining with antibody _____ is negative in normal adult melanocytes but offers additional specificity for examination of melanocytic neoplasms

HMB-45

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Reduced pigmentation of iris and retina
Photosensitivity
Decreased visual acuity
Nystagmus
Strabismus
Misrouting of optic nerve

Ocular albinism

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Cutaneous albinism (pigmentary dilution of skin and hair)
Ocular albinsim

Oculocutaneous albinism

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OCA: tyrosinase-negative (severe) albinism (complete loss of tyrosinase function)

OCA1A

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OCA: tyrosinase-positive (mild to moderate) albinism

OCA1B

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OCA: “Brown” albinism

OCA2

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OCA: “Rufous albinism”

OCA3

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OCA: variable degrees of albinism

OCA4

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Piebaldism
Congenital deafness
Heterochromia irides
Synophrys
Broad nasal root
Dystopia canthorum

Waardenburg syndrome

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WS: classic type

WS1

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WS: lacks dystopica canthorum

WS2

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WS: limb abnormalities (hypoplasia, syndactyly)

WS3

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WS: Hirschsprung disease

WS4

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Tyrosinase-positive cutaneous albinism
Deafness
Eyebrow hypoplasia

Tietz syndrome

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Depigmented forelock and abdominal skin

Piebaldism

``` Tyrosinase-positive oculocutaneous albinism (melanosome dysfunction) Bleeding diathesis (platelet granule dysfunction) ```

Hermansky-Pudlak syndrome

HPS: interstitial pulmonary fibrosis

HPS 1, 2, 4

HPS: granulomatous colitis

HPS 1, 4

HPS: neutropenia and cytotoxic T-cell dysfunction

HPS2

``` Tyrosinase-positive oculocutaneous albinism (melanosome dysfunction) Bleeding diathesis (platelet granule dysfunction) Progressive neurologic dysfunction (mechanism unknown) Severe immunodeficiency (NK cell, cytotoxic T cell, neutrophil dysfunction) Lymphomalike syndrome (overwhelming infiltration of organs by defective white blood cells) Giant lysosome-related organelles (these large granules are visible within leukocytes in PBS) ```

Chediak-Higashi syndrome

Pigmentary dilution of skin and hair (clumping of melanin within melanocytes)

Griscelli syndrome

GS: neurologic abnormalities

GS1

GS: immunodeficiency

GS2

Generalized patches of hyperpigmentation of skin and mucous membranes without systemic symptoms

Familial progressive hyperpigmentation

Diffuse hyperpigmented and hypopigmented patches without systemic symptoms Variable penetrance

Familial progressive hyper- and hypopigmentation

Eumalonosome stage: melanosomes are round, approximately 0.3 um in diameter, and contain small intraluminal vesicles reminiscent of multivesicular bodies of the early endosomal compartment

Stage I

Eumalonosome stage: melanosomes are oval in shape and approximately 0.5 um in diameter and exhibit deposition of a parallel fibrillar matrix

Stage II

Eumalonosome stage: melanosomes demonstrate deposition of pigment along the filaments

Stage III

Eumalonosome stage: melanosomes are fully melanized, with the electron-dense melanin completely obscuring the underlying structures

Stage IV

Pheomelanosomes exhibit similar ultrastructural stages of maturation with _____ pheomelansomes exhibiting melanization obscuring underlying structures

Late stage III and IV

(Pheo-/eumelanosomes) are smaller, retain a rounded morphology at all stages, and contain a disorganized and less dense filament network

Pheomelanosomes

Cutaneous interfollicular melanocytes are present at highest density in the _____, and at lower density in the skin of the _____

Facial and genital skin | Trunk and extremities

Characterized by a melanocyte and each of the keratinocytes that it physically contacts

Epidermal melanin unit

Each melanocyte contacts and delivers melanin to approximately _____ keratinocytes

Under the pathologic circumstance of nerve injury, _____ may undergo dedifferentiation to generate ectopic melanocytes

Schwann cells

Y/N: Within the hair follicle, the melanocyte population varies by the stage of the hair cycle

Yes

Melanocyte stem cells reside within the

Permanent bulge/secondary hair germ

During the anagen phase of the hair cycle, the McSCs become activated via

Wnt signaling

Differentiated melanocytes of the hair bulb undergo apoptosis during

Late catagen

Y/N: Gradual loss of McSC population occurs through each hair cycle

No - McSC population persists through each hair cycle

Y/N: Gradual loss of McSCs occurs with age

Yes

Has been demonstrated as a niche for McSCs of the acral epidermis

Lower permanent portion of the eccrine gland

Acral melanomas are diagnosed with high sensitivity and specificity as a result of their preferential pigmentation of the eccrine-rich _____ of the dermatoglyphs

Ridges

Synthesize melanin and form melanosomes but these cells are derived from the neuroectoderm and are developmentally unrelated to the neural crest/melanocyte lineage

Retinal pigment epithelium

(Lighter/Darker) eye pigmentation is associated with decreased incidence of age-related macular degeneration

Darker

Autoimmunity directed agains melanocytes can lead to severe CNS inflammation in

Vogt-Koyanagi-Harada syndrome

In the cochlea of the ear, melanocytes are located in and required for the normal development and function of the _____ layer

Stria vascularis

Sensorineural deafness | Pigmentation defects

Waardenburg and Tietz syndromes

Dysfunction of cardiac melanocytes predispose to

Arrhythmias

Melanocytes are exclusively derived from the highly migratiry and multipotent _____ population

Neural crest

Transient cell population that forms at the margin of the early forming neural tube

Neural crest

Neural crest cell migration between the somites and the ectoderm

Dorsolateral migration pathway

Second wave of melanocytes derived from Schwann cell precursors that migrate along developing nerves

Ventromedial migratory pathway

Melanocyte precursors

Melanoblasts

Master melanocyte transcription factor that is first expressed in melanoblasts shortly after exit from neural tube at embryonic day 10.5-11

MITF

Structure between the neural tube and somites where melanoblasts paude before traveling upon the dorsolateral migration pathwayl

Migration staging area

Other markers of melanoblast specification such as the melanogenic enzymes _____ are expressed during the dorsolateral migration

Dct | TYRP1

Melanocytes express the key melanigenic enzyme _____ by embryonic day 14.5

Tyrosinase

Melanocytes display pigmentation by embryonic day

16.5

Y/N: Most premigratory and migratory neural crest cells give rise to multiple cell types and likely retain developmental plasticity

Yes

Factors that regulate melanocyte development, survival and migration: transcription factors

``` MITF PAX3 SOX10 SOX2 FoxD3 ```

Germline mutations in _____ were identified in Waardenburg syndrome type 2, characterized by pigmentation defects and hearing loss

MITF (microphthalmia-associated transcription factor)

Defects in retinal pigment epithelium, osteoclasts, and mast cells Loss of melanocytes of the skin and inner ear

Microphthalmia

Most lineage selective in specifying melanocyte differentiation

MITF, in particular the melanocyte-specific isoform m-MITF)

Also regulate expression of other lineages, including certain muscle groups and enteric ganglia/neurons

SOX10 | PAX3

Mutation of _____ results in prominent pigment cell-related phenotypes wherease mutations of _____ produce pigment cell defects as well as certain nonpigmentary phenotypes (such as megacolon for _____)

MITF SOX10 and PAX3 SOX10

Required for the survival, proliferation and differentiation of melanocytes Acts as an oncogene and is amplifies in a subset of melanoma

MITF

The E318K MITF polymorphism found at low frequency in European, North American, and Australian populations is associated with significantly increased melanoma risk, an effect likely mediated by disruption of a concensus MITF _____ site

Sumoylation

One of the earliest markers of the neural crest Mutations result in pigmentation defects, abnormalities of neural crest derivatives of the sensory and sympathetic ganglia, Schwann cells, and cardiac neural crest Positive regulator of the MITF promoter in melanocytes and melanoma

PAX3 (Paired Box 3)

Mutated in human Waardenburg syndromes types 1 and 3 (hearing loss, pigmentation defect, arm and hand developmental defects)

PAX3

Required for the development of neural, glial, and melanocyte neural crest lineages First expressed in premigratory neural crest cells Loss leads to complete absence of melanoblasts Required for survival of postnatal melanocytes, melanocyte stem cells, nevi, and melanoma

SOX10 (SRY-Box 10)

One of 4 transcription factors required for reprogramming of somatic cells to induced pluripotent stem cells Play a role in specifying the melanocyte lineage during development Binds and represses the MITF promoter

SOX2

Factors that regulate melanocyte development, survival and migration: growth factor signaling

Ednrb c-Kit Wnt/Beta-Catenin Neuregulin/ErbB2/ErbB3

G-protein-coupled receptor that activates several signaling pathways, including PKC, MAPK and CAMP/PKA Does not seem to be required for the initial specification of melanoblasts; required mainly for proper melanoblast migration Induce melanocyte proliferation and skin pigmentation

Ednrb (endothelin receptor type B)

Ednrb agnosists, the endothelins, are encodes by 3 genes:

Edn1 Edn2 Edn3

Ednrb mutation results in

Hirschsprung disease

Edn3 mutation results in

Waardenburg plus megacolon

Upregulated during neural crest development and is important for establishing the neural crest lineage Loss leads to loss of most neural crest-derived stuctures Represses MITF to favor the Schwann cell fate

FoxD3 (Forkhead Box D3)

Mutated in Waardenburg type IV (Waardenburg plus megacolon)

SOX10

Also known as Steel factor or stem cell factor

cognate Kit ligand (KITLG)

KITLG exists in transmembrane and soluble forms and is produced by

Endothelial cells and keratinocytes

Mutation of c-Kit results in _____, which is characterized by a depigmentation of the forelock and abdominal skin

Piebaldism

Does not appear to be necessary for the specification of melanoblasts Deficiency results in melanoblasts soon disappearing after migration from the neural tube Regulating survival and differentiation/pigmentation of mature melanocytes

c-Kit

Polymorphisms in KITLG has been shown to cause

Familial progressive pigmentation | Familial progressive hyper- and hypopigmentation

Enlarging hyperpigmented patches corresponding to increased melanization without change in melanocyte number

Familial progressive pigmentation | Familial progressive hyper- and hypopigmentation

Activating mutations and amplification of c-Kit drive the progression of a subset of

Acral lentiginous, mucosal, and lentigo maligna melanomas

Consisting of APC, Axin1/2, and GSK3beta | Target beta-catenin for phosphorylation and ubiquitin-dependent degradation

Multiprotein membrane destruction complex

Binding of a Wnt family ligand to a _____ family receptor signals _____ to inhibit the membrane destruction complex, allowing for beta-catenin to enter the nucleus and to activate gene transcription

Frizzled | Dishevelled

Beta-catenin pathway activation also (potentiates/inhibits) melanoma formation and metastasis in mouse models

Potentiates

Controls Schwann cell proliferation, migration, and myelination

ErbB2/ErbB3 heterodimer tyrosine kinase receptor

ErbB2/ErbB3 heterodimer tyrosine kinase receptor ligand | Promotes Schwann cell fate and represses the melanocyte fate

Neuregulin

Factors that regulate melanocyte development, survival and migration: regulation of melanocyte motility and migration

Rac1

Belongs to the Rho superfamily of GTPases | When deleted, melanoblasts migrate less efficiently

Rac1

Mutation of _____, a guanine nucleotide exchange factor, occurs frequently in human melanomas, and these mutations may promote melanoma through activation of Rac1

PREX2

The 2 forms of melanin, eumelanin | and pheomelanin, are both derived from the precursor

Tyrosine

Tyrosinase converts tyrosine to

Dopaquinone

Brown/black melanin

Eumelanin

Yellow/orange melanin

Pheomelanin

Composed of polymers of 5,6-dihydroxyindole and the carboxylate form 5,6-dihydroxyindole-2-carboxylic acid

Eumelanin

Formed by oxidation and polymerization of sulfur-containing cysteinyldopa

Pheomelanin

Eu- vs pheomelanin: may act as a pro-oxidant

Pheomelanin

UVA interacts with pheomelanin, and to a lesser extent, eumelanin, leading to melanin degradation products that induce CPD formation long after UV exposure has ended

Dark CPD

Tyrosinase requires binding of ______ for proper function

Copper

Two tyrosine-related proteins, _____, show significant homology to tyrosinase and play key roles in melanogenesis (proper trafficking and stabilization of tyrosinase)

TYRP1 | TYRP2/Dopachrome tautomerase (DCT)

Defects of tyrosinase, TYRP1, and DCT cause

Oculocutaneous albinism

Eumelanogenesis: Dopaquinone spontaneously undergoes intramolecular cyclization to form

Cyclodopa

Eumelanogenesis: Cyclodopa then undergoes redox exchange with a second molecule of dopaquinone to form

Dopachrome | Dopa

Eumelanogenesis: Dopachrome spontaneously decarboxylates to form _____ (less soluble, black) and _____ (more soluble, lighter black/brown)

DHI | DHICA

Eumelanogenesis: Although the uncatalyzed reaction favors DHI formation, the presence of the _____ favors production of DHICA

(DCT) protein

Eumelanogenesis: DHI and DHICA are then oxidized and polymerized to form

Eumelanin

Eumelanogenesis: _____ exhibits DHICA-oxidase activity, promoting incorporation of DHICA into eumelanin

TYRP1

Pheomelanogenesis: Nonenzymatic addition of sulfhydryl groups to dopaquinone results in the formation of

5-S-cysteinaldopa | 2-S-cysteinaldopa

Pheomelanogenesis: _____ serves as a major source of sulfhydryl groups, with the other source being ______

Cysteine | Glutathione

Cysteinaldopa synthesis predominates in the presence of ______, whereas high tyrosine and/or low cysteine favor ______

Cysteine | Eumelanogesis

Pheomelanogenesis: Cysteinaldopa then undergoes redox exchange with dopaquinone to produce

Cysteinaldopaquinones

Pheomelanogenesis: Oxidation and cyclization of cysteinaldopaquinones is followed by dehydation, rearrangement, and decarboxylation to form

Benzothiazole intermediates

Pheomelanogenesis: The benzothiazole intermediates then polymerize to form

Pheomelanin

Melanosomes are lysosome-related organelles that exist only in

Melanocytes | Retinal pigment epithelium

As melanosomes mature, the key ultrastructural feature is the appearance of the

Parallel fibrillar network

Pigment cell-specific protein that has been shown to be the main component of the parallel fibrillar network

PMEL (gp100 or silver)

First site of PMEL deposition

Intraluminal vesicles of stage I melanosomes

Increased organization of PMEL amyloid into visible proteinaceous fibrils, which push the intraluminal vesicles outward to fuse with the melanosome membrane

Stage II melanosomes

Become increasingly pigmented as melanogenic enzymes are delivered and melanin synthesis has ceases

Stage III melanosomes

Fully pigmented, and tyrosinase activity and melanin synthesis has ceased

Stage IV melanosome

Mutations of any of the 10 genes encoding components of the BLOC-1, BLOC-2, BLOC-3, and AP-3 protein complexes have been long known to be responsible for

Hermansky-Pudlak syndrome

Hypopigmentation due to melanosome dysfunction in addition to platelet dysfunction, immunodeficiency, and lung fibrosis due to abnormalities of other lysosome-related organelles

Hermansky-Pudlak syndrome

Coordinated the action of microtubule- and actin-dependent machineries to allow proper formation and stabilization of recycling endosomal tubules required for transfer of cargoes to melanosomes

BLOC1

Acts to properly direct recycling endosomal tubular transport intermediates to maturing melanosomes to promote melanogenic cargo delivery

BLOC-2

Also important for sorting cargo proteins bound for melanosomes, and in different scenarios can act in concert with or independently of BLOC complexes

AP-3

The final step in the delivery of cargo to melanosomes is the fusion of cargo-containing vesicle and tubules with the developing melanosome. This involve _____ that are required for membrane fusion

SNARE protein

SNARE responsible for BLOC-1-dependent delivery of TYRP1 to the melanosome

VAMP7

Is required for the subsequent recycling of VAMP7 after delivery of cargo to the melanosome

BLOC-3

Stage IV melanosomes are first transferred to the dendrite tips by _____-mediated microtubule-dependent anterograde transport. _____-mediated retrograde transport melanosomes away from the melanocyte dendrites have been reported

Kinesin | Dynein

GTPase _____ is incorporated into the melanosome membrane by a hydrophobic geranylgeranyl tail

Rab27a

The adapter protein _____ binds Rab27a and serves a linker to the actin-binding motor protein _____, following transport and retention of melanosomes on the actin cytoskeleton

Melanophilin (Mlph) | MyosinVa (MyoVa)

Mutations in Rab27a, Mlph, and MyoVa have been identified in

Griscelli syndrome (partial albinism and immunodeficiency)

Melanosomes are transferred by dynein-mediated retrograde transport to a perinuclear location (“_____”) to protect basal keratinocytes from UV-induced DNA damage

Nuclear capping

In (dark-/light-) skinned individuals, melanosomes are smaller, and are grouped in membrane-enclosed clusters of 4-8 melanosomes

Light

In (darker-/lighter-) skinned individuals, melanosomes are larger, more numerous, and are distributed individually

Darker

Y/N: Melanosomes are thought to be degraded during the keratinocyte terminal differentiation process

Yes

Keratinocytes derived from (darker-/lighter-) skinned individuals degrade melanosomes more slowly

Darker

G-protein-coupled receptor expressed primarily by melanocytes Critical role in determining if a melanocyte produces predominantly eumelanin or pheomelanin

MC1R (melanocortin 1 receptor)

(Gain-/Loss-) of-function variants of MC1R are associated with the “red hair phenotype”

Loss

Canonical agonist for MC1R

Alpha-melanocyte stimulating hormone

Alpha-MSH is derived from proteolytic processing of its precursor

Proopiomelanocortin (POMC)

_____ gene mutation, in addition to endocrine dysfunction, display the red hair phenotype

POMC

Antagonist of MC1R signaling

Agouti protein

Transcriptionally activated by MITF in melanocytes and serves as a negative feedback regulator that degrades cAMP

Phosphodiesterase D4

Human pigmentation is categorized into

Constitutive and inducible responses

Inducible pigmentation after UV exposure (sun tanning) has 2 components that are wavelength dependent

Immediate tanning | Delayed tanning

Immediate tanning occurs within minutes to hours after sun exposure, and is mainly a response to _____ radiation. It is most noticeable in _____-skinned individuals and is mediated by oxidation and redistribution of existing melanin

UVA | Darker

Delayed tanning is mainly a response to _____ and peaks at about 3 days to 1 week after sun exposure

UVB and shorter-wavelength UVA

Immediate vs delayed tanning: much more protective against subsequent sun exposure

Delayed

Y/N: Pigmentary pathways downstream of a defective MC1R remain intact

Yes

UV radiation of keratinocytes (increases/decreases) TGFbeta1 production

Decreases