Melanocytes/ Pigment Flashcards
1
Q
Embryonic origin of melanocytes
A
Neural crest
2
Q
Transcription factor expressed by transient neural crest cells
A
SOX10
3
Q
Gene important for specifying melanoblasts
A
**MITF
+PAX3
(downregulation of FOXD3)
4
Q
Cell signals for differentiation from melanoblast to melanocyte
A
Wnt
KIT/SCF
Endothelin 3/EDNRB
FGF
BMP
E-cadherin, P cadherin
5
Q
Locations of melanocytes throughout body
A
Skin
Oral mucosa
Eyes
Leptomeninges
Ear
6
Q
Location of non-melanocyte transient neural crest cells
A
Facial connective tissues
Heart
GI nervous system
7
Q
Disorders of melanoblast migration (3)
A
- Piebaldism
-white spots on midline, normal ears/eyes - Waardenburg syndrome
-white coat, eyes/ears/muscle/etc affected
-Lethal white foal syndrome (EDNRB), megacolon - Tietz syndrome (MITF)
-white coat, eyes, deaf + microophalmia
8
Q
Gene for piebaldism in brown swiss cattle, holstein, Simmental cattle
A
MITF
9
Q
Gene for piebaldism in Birman cat (white glove), white spots in horses, cattle, pigs
A
KIT
10
Q
Gene for white belting in cows
A
TWIST2
11
Q
Gene for roan color in Belgian blue cattle, short horned cattle
A
SCF/KITLG
12
Q
Genes (2) for increased digital SCC in poodles, Giant Schnauzers
A
MC1R
KITLG
13
Q
Gene for coat color intensity
A
KITLG (# of copies of the gene)
14
Q
Genes (2) for waardenburg syndrome in dogs
A
MITF, SILV
15
Q
Genes for waardenburg syndrome in cats
A
KIT
16
Q
Genes for waardenburg syndrome in cattle, pigs
A
MITF
17
Q
Genes (3) for waardenburg syndrome in horses
A
EDNRB
PAX3
MITF
18
Q
Gene for lethal white foal syndrome, lethal white lamb syndrome
A
EDNRB
19
Q
Waardenburg type___ = lethal white foal syndrome
A
4
20
Q
Clinical signs of lethal white foal syndrome
A
White coat, aganglionic megacolon
21
Q
Piebaldism: clinical signs
A
White coat
Eyes/ears normal
22
Q
Waardenburg syndrome: clinical signs:
A
White coat, senorineural deafness, depigmented iris, other NCC disorders
23
Q
Tietz syndrome gene in cow
A
MITF
24
Q
Clinical sign of Tietz syndrome in cow
A
White head, eyes, deaf
+ Microophthlamia
(overlap w/Waardenburg type 2)
25
Where are melanocyte stem cells in the skin?
Hair follicle (bulge), epidermis (basale), dermis, eccrine sweat glands
26
Cell signal to localize melanocyte stem cells to hair bulge (to live with keratinocyte stem cells!)
KIT/KIT-L interactions with keratinocytes!
(+cadherins, integrins, COL17)
27
Cell signal to localize melanocytes to anagen hair bulb (by keratinocytes)
KIT (melanocyte)/KIT-L (keratinocyte)
28
Cell signals for melanocyte stem cell interactions with the hair follicle
Wnt
B-RAF C-RAF
NOTCH
TGF-B
BDN
NFIB
29
What happens if melanocytes aren't distributed evenly throughout the hair bulb
dilute coat color
(ie ancient horses)
30
How does TBX3 affect hair shaft color?
TBX3 suppresses KIT-L on keratinocytes
--> melanocytes are not recruited to the hair bulb
*Modern horses have mutation to inactivate TBX3, resulting in more robust hair color
31
2 incidents that can recruit melanocytes from follicle to epidermis
1) Wounding
2) UVB irradiation
32
Cell signal to recruit melanocytes from follicle to epidermis
MC1R
33
Damage to which type of cell can also cause injury to melanocytes --> causing greying
Ketatinocyte stem cells
*Share a niche in the bulge*
34
Which drug has been associated with reversible hair graying?
Tyrosine kinase KIT inhibitors --> Palladia
35
Autosomal dominant mutation of STX17 results in which phenotype?
Gray horse phenotype --> Premature graying
36
Gray horse phenotype mode of inheritance
Autosomal dominant
37
Gray horse phenotype gene
STX17
38
How old are grey horses when they lose nearly all their hair pigment?
Age 6-8 yrs old
39
What percent of grey horses develop cutaneous melanomas by age 15?
70-80%
40
What cancer are grey horses overrepresented for?
Cutaneous melanoma
41
What gene OTHER than STX17 is likely responsible for grey coat phenotypes in horses? (melanoma formation, vitiligo-like depigmentation, speckling)
ASIP
42
Etiology of grey horse phenotype?
Defect in hair follicle melanocyte stem cell survival
43
Which body parts receive melanosomes from keratinocytes?
Epidermis, hair follicle, mucosae
44
Melanosomes are lysosome-related organelles (LRO). Name 2 others
-Platelet dense granules
-Type II pneumocyte lamellar bodies
45
Eumelanin color
Black/brown
46
Pheomelanin color
Yellow/red
47
Stage I melanosome formation
Formation of organelle vesicle structure
(build the restaurant)
48
Stage II melanosome formation
-Put in supportive protein fibrils, which gives melanosome its shape
-Add enzymes to make the melanin; derived from golgi
Fibril function: support + shaping (premelanosome protein 17 **[SILV]**
+ MART-1, GPNMB)
(hire the servers)
49
Stage III melanosome formation
Melanin deposited along fibrils, but you can still see the fibrils
(make a few pizzas, soft open)
50
Stage IV melanosome formation
Melanosome is full of pigment, can no longer see fibrils
(Restaurant is a success. Full of pizzas)
51
Hermansky Pudlak Syndrome clinical signs
White coat, hypopigmented eyes, leukocyte problems!
"Pud Lacking blood"
52
Why do dogs with Hermansky Pudlak Syndrome also have blood cell issues?
Melanosomes and platelet dense granules have similar Lysosomal related organelle biomechanics
53
IHC targets for melanocytes, melanomas
Tyrosinase
MITG
Melan-A/Mart1
Also Vimentin, S-100
54
When are melanocytes activated during hair cycle
Anagen
55
Which cell signal is important for activating melanocytes during anagen
Wnt
56
What is the common precursor to both eumelanin and pheomelanin?
Dopaquinone
57
Main protein fibril in melanosomes
Premelanosome protein 17 (SILV)
58
Which cells other than melanocytes have LROs (lysosome related organelles)?
Platelets
Neutrophils
T cells
Type II pneumocytes
59
Other name for Gray Collie syndrome
Canine Cyclical Hematopoiesis
60
Clinical signs of Gray Collie syndrome/ Canine Cyclical Hematopoiesis
-Dilute skin/hair coat
-Cyclical neutropenia, thromocytopenia, anemia
-Recurrent infections
*-Grey/dilute nasal planum*
61
Cause of dilute coat in grey collie syndrome
Inadequate delivery of melanin synthesis enzymes from golgi to melanosome --> decreased melanization of melanosomes
62
Gene causing grey collie syndrome (HPS type 2)
*AP3B1*
(B1 subunit of the AP-3 complex that delivers biosynthesis enzymes from golgi to melanosome)
63
Coat color phenotye associated with HPS type 3 in French bulldogs (decreased platelet dense granules w/o bleeding)
Cocoa coat color
64
Gene mutation causing HPS type 3 of French bulldogs (decreased platelet dense granules w/o bleeding)
BLOC gene mutation (important for transportation of biosynthesis enzymes from golgi to melanosome)
65
Which breed with a cocoa coat phenotype develops HPS type 3 (decreased platelet dense granules w/o bleeding)
French bulldogs
66
Which breed of cat gets HPS type 5, BLOC-2 complex mutation
Donskoy cats
67
What color are Donskoy cats with HPS type 5, BLOC-2 complex mutation
Light brown skin, yellow irises, red-eye effect
68
Other than cats, which other animal also has HPS type 5
Horses with white markings
No deleterious effects
69
What does HPS stand for?
Hermansky-Pudlak syndrome
70
Gene mutation in *AP3B1* causes _____
Gray Collie syndrome (canine cyclical hemtopoesis)
71
Mutation causing Merle coat color
SILV
72
Chediak-Higashi syndrome: clinical signs
-Hypopigmentation of hair, skin, eyes with silvery sheen
-Severe immunodeficiency
-Recurrent infections
-Neurologic signs
-Bleeding
-Pulmonary fibrosis
73
Chediak Higashi syndrome: gene mutations, function
CHS/LYST (lysosomal trafficking regulator) --> regulates vesicle fusion with plasma membrane
74
Histopathologic finding CLASSIC for Chediak Higashi syndrome
*Neutrophils with large granules*
Giant, intracytoplasmic accumulations of granular material, because can't fuse with cell membrane
*Also happens in other cells*
75
Chediak Higashi syndrome: species
Hereford/Brangus/Japanese black cattle, **Persian cats**, beige mice, beige rats, minks, silver/blue foxes, killer wale
76
Clinical signs of dogs with Merle coat color 2' SILV mutation
Congenital sensorineural deafness, blue irises
77
Equine multiple congenital ocular anomalies (silver, silver dapple horses) gene
SILV
78
Rat-tail syndrome (color dilution and hypotrichosis in calves) gene
SILV
79
Congenital Stationary Night Blindness + leopard spotting gene
TRPM1
(channel protein that affects melanocyte survival, retinal cell function)
80
True or false: melanin pigment can be cytotoxic if not contained in an organelle
TRUE!!!
81
Important cofactor for tyrosinase
Copper
82
Which enzyme is copper a cofactor for?
Tyrosinase
83
What is the rate limiting step of melanin synthesis
Tyrosinase
(L-tyrosine to L-Dopa)
(L-Dopa to Dopaquinone)
84
Which enzyme is required to convert Dopachrome to DHICA
TYRP2
85
Which enzyme is required to convert DHICA to eumelanin
TYRP1
86
Which amino acid needs to be available in high levels to make Pheomelanin
Cysteine
87
Cysteine is required for synthesis of which: eumelanin or pheomelanin
Pheomelanin
88
Is TYRP1 important for synthesis of eumelanin or pheomelanin?
Eumelanin
89
Pigment type switching (eumelanin to pheomelanin, etc) results in _____
Agouti coat
90
Agouti protein antagonizes ____ to promote pheomelanin
α-MSH
91
MC1R binds α-MSH to promote ______ (melanin type)
Eumelanin
92
T or F: animals with oculocutaneous albinism are deaf
FALSE
(have melanocytes, they just don't make melanin. Disorder of melanin synthesis)
93
In addition to hypomelanosis of tissue, which other clinical sign is seen in many cases of oculocutaneous albinism?
Nystagmus
94
Which animal has nystagmus 2' their oculocutaneous albinism?
Siamese cats
95
Mutation associated siamese coat (oculocutaneous albinism type 1), recessive
Tyrosinase (TYR)
96
Cat breeds with oculocutaneous albinism
**Siamese**
*Burmese* -> Mocha
Birman
Balinese
Himalayan
97
Oculocutaneous albinism type 2 in Doberman Pinscher gene. "White Doberman"
SLC45A2
98
Disease associated with a mutation in SLC45A2 (OCA type 2)
White doberman pinscher
**Increased risk of melanoma**
99
Potential risk factor with white dobermans
Increased risk of melanoma
SLC45A2
100
OCA type 1 gene
Tyrosinase (affect both eumelanin and pheomelanin)
101
OCA type 2 gene
TYRP1 (eumelanin only affected)
102
Which amino acids are crucial in the diet for appropriate pigmentation (2)
Phenylalanine
Tyrosine
103
Result of diet deficient in phenylalanine or tyrosine
Discoloration of hairs
104
Which element is crucial in the diet for appropriate pigmentation (1)
Copper
105
Copper deficient diet results in _____
"Ghost eyes" "Spectacle disease"
Graying of periocular hair
Coat greying in puppies
106
"Ghost eyes" etiology
diet deficient in copper
107
Epidermal melanin unit
1 melanocyte transfering melanosomes to 36 keratinocytes
108
Follicular melanin unit
1 melanocyte transfering melanosomes to 5 keratinocytes
109
Dendrites of melanocytes reach as high as ___ in the epidermis
Stratum spinosum
110
Proteins at dendrite tip of melanocyte, to transfer melanosome (3)
1) Rab27a
2) Melanophilin
3) Myosin-5a
111
Which level of epidermis has the most melanosomes
Stratum basale
112
Where does small melanosomes live within a keratinocyte?
Perinuclear cap
(microparasol)
113
Where do large melanosomes live within a keratinocyte?
Throughout cytoplasm
114
Mechanism that brings small melanosomes to perinuclear cap
Melanosome is endocytosed --> dynactin, dynein motor along microtubules to the correct spot
115
Genes implicated in Griscelli syndrome
MLPH, Myosin5a, Rab27a
Tips of melanocyte dendrites
116
Lavendar foal syndrome gene
Myo5a
117
Histopath from patient w/Lavendar foal syndrome
Clumped melanosome in cell bodies of melanocytes
118
Clinical signs Lavendar foal syndrome
Dilute coat, neurologic signs, lethal
119
Dog breed with Myo5a disease, GS type-1
Mini dachshunds
Dilute coat, neuro signs
120
Gene associated with color dilution alopecia
MLPH
D locus
121
Is MLPH mutation alone enough to induce CDA?
No. Other modifying factors required
122
Causes for hyperpigmentation (acquired) (3)
Solar
Inflammation
Pharmacologic (rubber?)
123
Causes of hypopigmentation by affecting both keratinocytes and melanocytes (acquired)
Trauma: burns, wounds, etc.
Disrupt epidermal and follicular melanin units
124
Causes of hypopigmentation by targeting melanocytes (3)
-Vitiligo
-Uveodermatologic syndrome (also targets keratinocytes)
-Alopecia areata (also targets keratinocytes)
125
Causes of hypopigmentation by epidermal cytotoxic disorders (4 +3 bonus)
-Keratinocyte viral infections
-CLE
-EM
-SJS/TEN
*also vascular/ischemic, CETL, AISBD
126
MITF increases transcription of ___ (4)
Tyrosinase
DOPA
TYRP1
TYRP2
127
Main adhesion molecule expressed by melanocytes to connect to the skin.
E-cadherin
128
Where are melanocytes in the ear?
Cochlea (Stria vascularis)
129
Special stains to visualize melanocytes
Fontana Masson, DOPA oxidase reaction, Schmorl's method
130
Specialized cell for amphibian, fish, reptile, cephalodpod pigmentation
Chromatophores
-Reflect light in different ways to determine coloration
131
Cytokines released by melanocytes in inflammation
IL-8
IL-1α
TNFα
132
Do melanocytes increase or inhibit keratinocyte proliferation?
INHIBIT
133
Major difference between eumelanin and pheomelanin (chemically)
Pheomelanin has high sulfur
(yellow, like stinky eggs)
134
Cell signal primarily responsible for regulation of melanogenesis
MITF
135
How does UV radiation stimulate melanogenesis?
UV upregulates POMC, α-MSH, ACTH, and MC1R.
POMC is cleaved into α-MSH. α-MSH binds to MC1-R on melanocyte surface --> increases cAMP --> signal cascade --> upregulates MITF (tyr, tyrp1, more melanin!)
136
POMC is a precursor for α-MSH, which induces melanin synthesis. What else is POMC a precursor for?
ACTH
(ACTH can also increase cAMP, leading to more MITF expression/more melanin)
137
What is the agonist of MC1R
α-MSH
138
What is the antagonist of MC1R
agouti protein
(binds with higher affinity than α-MSH, producing pheomelanin instead)
139
Does α-MSH produce pheomelanin or eumelanin
eumelanin
(Agouti is antagonist for MC1R, which switches to pheomelanin)
140
Stimulators of melanogenesis (10)
1) α-MSH
2) ACTH
3) Endothelin 1
4) SCF
5) Leukotrienes (LTB4, LTC4)
6) Prostaglandins (PGE2, PGF2α)
7) UV radiation
8) Nitric oxide
9) Histamine
10) eutroprophins
141
Inhibitors of melanogenesis (3)
IL-1
IL-6
TNF-α
142
Inhibitor of differentiation from neural crest cells to melanocytes
BMP-4
143
Disease from breeding two Overo spotted paint horses (EdnrB)
Lethal white foal syndrome
144
Mode of inheritance Lethal white foal syndrome
Autosomal recessive
145
Who makes larger melanosomes: follicular or epidermal melanocytes?
Follicular
146
Disease of "Blaze" colored ferrets
Waardenburg syndrome
Flat skulls, wide set eyes, white stripe on top of head
147
Breed with LYST mutation, Chediak Higashi syndrome
Persian cats
148
Breed with lethal lavendar foal syndrome
Arabian horses
149
Breeds with hereditary vitiligo
Belgian Tervuren dogs
Rottweilers
Old English Sheepdogs
150
Dog breeds with vitiligo (+1 cat, + 1 horse)
Rottweiler, Doberman, Collie
Siamese
Arabian horse
151
Cells involved in vitiligo
CD8+ T cell attack at melanocytes (Melan-A)
Also NK cells, antibodies (against TYR, TRP1, TRP2)
152
Uveodermatologic target
Tyrosinase, TYRP1, TYRP2
Also gp100 in melanocytes
153
Histopath finding vitiligo
loss of melanocytes from the epidermis and/or hair follicle. Keratinocytes lack melanosomes
+pigmentary incontinence+ melanophages
+rare: lymphocytes around apoptotic melanocytes
154
3 phases of uveodermatologic syndrome in humans
1) Meningoencephalic phase: headaches, seizures, vomit
2) Acute ophthalmic phase: photophobia, eye pain, uveitis, retinal detachment
3) Dermatologic phase: vitiligo, poliosis, alopecia
155
Uveodermatologic syndrome breed
Akita
156
Equine leukoderma differentials (10)
1) Onchocerciasis
2) Dourine
3) Herpes coital exanthema
4) Lupus erythematosis
5) Pressure sores (saddle)
6) Ear papillomas
7) Ventral midline dermatitis
8) Regressing viral papillomatosis
9) Freezing/burning
10) Contact phenols/ rubber
157
Equine leukotrichia gene
Dominant W allele- albino, blano, cremello
158
Potential vitiligo variant in horses
Acquired idiopathic leukotrichia, aka "spotted leukotrichia"
Breeds: Thoroughbred, Shire, Arabians
159
Why are melanocytes important for hearing?
Melanocytes maintain the K+ potential in endolymph of the cochlea
MITF needed for cochlea development
160
What TF causes follicular melanocytes to proliferate and mature
SCF/c-kit
Released by follicular keratinocytes
161
Cause of Congenital Hereditary Sensorineural Deafness in Dalmations
Deafness = result of strial degeneration --> absence of strial melnocytes
-Dalmations
Piebald gene
(Also merle gene, but different breeds like Aussies!)
