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EV ACVD Study > Melanocytes/ Pigment > Flashcards

Melanocytes/ Pigment Flashcards

1
Q

Embryonic origin of melanocytes

A

Neural crest

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2
Q

Transcription factor expressed by transient neural crest cells

A

SOX10

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3
Q

Gene important for specifying melanoblasts

A

**MITF
+PAX3
(downregulation of FOXD3)

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4
Q

Cell signals for differentiation from melanoblast to melanocyte

A

Wnt
KIT/SCF
Endothelin 3/EDNRB
FGF
BMP
E-cadherin, P cadherin

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5
Q

Locations of melanocytes throughout body

A

Skin
Oral mucosa
Eyes
Leptomeninges
Ear

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6
Q

Location of non-melanocyte transient neural crest cells

A

Facial connective tissues
Heart
GI nervous system

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7
Q

Disorders of melanoblast migration (3)

A
  1. Piebaldism
    -white spots on midline, normal ears/eyes
  2. Waardenburg syndrome
    -white coat, eyes/ears/muscle/etc affected
    -Lethal white foal syndrome (EDNRB), megacolon
  3. Tietz syndrome (MITF)
    -white coat, eyes, deaf + microophalmia
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8
Q

Gene for piebaldism in brown swiss cattle, holstein, Simmental cattle

A

MITF

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9
Q

Gene for piebaldism in Birman cat (white glove), white spots in horses, cattle, pigs

A

KIT

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10
Q

Gene for white belting in cows

A

TWIST2

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11
Q

Gene for roan color in Belgian blue cattle, short horned cattle

A

SCF/KITLG

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12
Q

Genes (2) for increased digital SCC in poodles, Giant Schnauzers

A

MC1R
KITLG

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13
Q

Gene for coat color intensity

A

KITLG (# of copies of the gene)

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14
Q

Genes (2) for waardenburg syndrome in dogs

A

MITF, SILV

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15
Q

Genes for waardenburg syndrome in cats

A

KIT

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16
Q

Genes for waardenburg syndrome in cattle, pigs

A

MITF

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17
Q

Genes (3) for waardenburg syndrome in horses

A

EDNRB
PAX3
MITF

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18
Q

Gene for lethal white foal syndrome, lethal white lamb syndrome

A

EDNRB

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19
Q

Waardenburg type___ = lethal white foal syndrome

A

4

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20
Q

Clinical signs of lethal white foal syndrome

A

White coat, aganglionic megacolon

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21
Q

Piebaldism: clinical signs

A

White coat
Eyes/ears normal

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22
Q

Waardenburg syndrome: clinical signs:

A

White coat, senorineural deafness, depigmented iris, other NCC disorders

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23
Q

Tietz syndrome gene in cow

A

MITF

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24
Q

Clinical sign of Tietz syndrome in cow

A

White head, eyes, deaf
+ Microophthlamia

(overlap w/Waardenburg type 2)

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25
Q

Where are melanocyte stem cells in the skin?

A

Hair follicle (bulge), epidermis (basale), dermis, eccrine sweat glands

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26
Q

Cell signal to localize melanocyte stem cells to hair bulge (to live with keratinocyte stem cells!)

A

KIT/KIT-L interactions with keratinocytes!
(+cadherins, integrins, COL17)

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27
Q

Cell signal to localize melanocytes to anagen hair bulb (by keratinocytes)

A

KIT (melanocyte)/KIT-L (keratinocyte)

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28
Q

Cell signals for melanocyte stem cell interactions with the hair follicle

A

Wnt
B-RAF C-RAF
NOTCH
TGF-B
BDN
NFIB

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29
Q

What happens if melanocytes aren’t distributed evenly throughout the hair bulb

A

dilute coat color

(ie ancient horses)

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30
Q

How does TBX3 affect hair shaft color?

A

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

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31
Q

2 incidents that can recruit melanocytes from follicle to epidermis

A

1) Wounding
2) UVB irradiation

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32
Q

Cell signal to recruit melanocytes from follicle to epidermis

A

MC1R

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33
Q

Damage to which type of cell can also cause injury to melanocytes –> causing greying

A

Ketatinocyte stem cells

Share a niche in the bulge

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34
Q

Which drug has been associated with reversible hair graying?

A

Tyrosine kinase KIT inhibitors –> Palladia

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35
Q

Autosomal dominant mutation of STX17 results in which phenotype?

A

Gray horse phenotype –> Premature graying

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36
Q

Gray horse phenotype mode of inheritance

A

Autosomal dominant

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37
Q

Gray horse phenotype gene

A

STX17

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38
Q

How old are grey horses when they lose nearly all their hair pigment?

A

Age 6-8 yrs old

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39
Q

What percent of grey horses develop cutaneous melanomas by age 15?

A

70-80%

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40
Q

What cancer are grey horses overrepresented for?

A

Cutaneous melanoma

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41
Q

What gene OTHER than STX17 is likely responsible for grey coat phenotypes in horses? (melanoma formation, vitiligo-like depigmentation, speckling)

A

ASIP

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42
Q

Etiology of grey horse phenotype?

A

Defect in hair follicle melanocyte stem cell survival

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43
Q

Which body parts receive melanosomes from keratinocytes?

A

Epidermis, hair follicle, mucosae

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44
Q

Melanosomes are lysosome-related organelles (LRO). Name 2 others

A

-Platelet dense granules
-Type II pneumocyte lamellar bodies

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45
Q

Eumelanin color

A

Black/brown

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46
Q

Pheomelanin color

A

Yellow/red

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47
Q

Stage I melanosome formation

A

Formation of organelle vesicle structure

(build the restaurant)

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48
Q

Stage II melanosome formation

A

-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)

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49
Q

Stage III melanosome formation

A

Melanin deposited along fibrils, but you can still see the fibrils

(make a few pizzas, soft open)

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50
Q

Stage IV melanosome formation

A

Melanosome is full of pigment, can no longer see fibrils

(Restaurant is a success. Full of pizzas)

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51
Q

Hermansky Pudlak Syndrome clinical signs

A

White coat, hypopigmented eyes, leukocyte problems!

“Pud Lacking blood”

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52
Q

Why do dogs with Hermansky Pudlak Syndrome also have blood cell issues?

A

Melanosomes and platelet dense granules have similar Lysosomal related organelle biomechanics

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53
Q

IHC targets for melanocytes, melanomas

A

Tyrosinase
MITG
Melan-A/Mart1

Also Vimentin, S-100

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54
Q

When are melanocytes activated during hair cycle

A

Anagen

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55
Q

Which cell signal is important for activating melanocytes during anagen

A

Wnt

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56
Q

What is the common precursor to both eumelanin and pheomelanin?

A

Dopaquinone

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57
Q

Main protein fibril in melanosomes

A

Premelanosome protein 17 (SILV)

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58
Q

Which cells other than melanocytes have LROs (lysosome related organelles)?

A

Platelets
Neutrophils
T cells
Type II pneumocytes

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59
Q

Other name for Gray Collie syndrome

A

Canine Cyclical Hematopoiesis

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60
Q

Clinical signs of Gray Collie syndrome/ Canine Cyclical Hematopoiesis

A

-Dilute skin/hair coat
-Cyclical neutropenia, thromocytopenia, anemia
-Recurrent infections
-Grey/dilute nasal planum

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61
Q

Cause of dilute coat in grey collie syndrome

A

Inadequate delivery of melanin synthesis enzymes from golgi to melanosome –> decreased melanization of melanosomes

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62
Q

Gene causing grey collie syndrome (HPS type 2)

A

AP3B1

(B1 subunit of the AP-3 complex that delivers biosynthesis enzymes from golgi to melanosome)

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63
Q

Coat color phenotye associated with HPS type 3 in French bulldogs (decreased platelet dense granules w/o bleeding)

A

Cocoa coat color

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64
Q

Gene mutation causing HPS type 3 of French bulldogs (decreased platelet dense granules w/o bleeding)

A

BLOC gene mutation (important for transportation of biosynthesis enzymes from golgi to melanosome)

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65
Q

Which breed with a cocoa coat phenotype develops HPS type 3 (decreased platelet dense granules w/o bleeding)

A

French bulldogs

66
Q

Which breed of cat gets HPS type 5, BLOC-2 complex mutation

A

Donskoy cats

67
Q

What color are Donskoy cats with HPS type 5, BLOC-2 complex mutation

A

Light brown skin, yellow irises, red-eye effect

68
Q

Other than cats, which other animal also has HPS type 5

A

Horses with white markings
No deleterious effects

69
Q

What does HPS stand for?

A

Hermansky-Pudlak syndrome

70
Q

Gene mutation in AP3B1 causes _____

A

Gray Collie syndrome (canine cyclical hemtopoesis)

71
Q

Mutation causing Merle coat color

A

SILV

72
Q

Chediak-Higashi syndrome: clinical signs

A

-Hypopigmentation of hair, skin, eyes with silvery sheen
-Severe immunodeficiency
-Recurrent infections
-Neurologic signs
-Bleeding
-Pulmonary fibrosis

73
Q

Chediak Higashi syndrome: gene mutations, function

A

CHS/LYST (lysosomal trafficking regulator) –> regulates vesicle fusion with plasma membrane

74
Q

Histopathologic finding CLASSIC for Chediak Higashi syndrome

A

Neutrophils with large granules

Giant, intracytoplasmic accumulations of granular material, because can’t fuse with cell membrane
Also happens in other cells

75
Q

Chediak Higashi syndrome: species

A

Hereford/Brangus/Japanese black cattle, Persian cats, beige mice, beige rats, minks, silver/blue foxes, killer wale

76
Q

Clinical signs of dogs with Merle coat color 2’ SILV mutation

A

Congenital sensorineural deafness, blue irises

77
Q

Equine multiple congenital ocular anomalies (silver, silver dapple horses) gene

A

SILV

78
Q

Rat-tail syndrome (color dilution and hypotrichosis in calves) gene

A

SILV

79
Q

Congenital Stationary Night Blindness + leopard spotting gene

A

TRPM1
(channel protein that affects melanocyte survival, retinal cell function)

80
Q

True or false: melanin pigment can be cytotoxic if not contained in an organelle

A

TRUE!!!

81
Q

Important cofactor for tyrosinase

A

Copper

82
Q

Which enzyme is copper a cofactor for?

A

Tyrosinase

83
Q

What is the rate limiting step of melanin synthesis

A

Tyrosinase

(L-tyrosine to L-Dopa)
(L-Dopa to Dopaquinone)

84
Q

Which enzyme is required to convert Dopachrome to DHICA

A

TYRP2

85
Q

Which enzyme is required to convert DHICA to eumelanin

A

TYRP1

86
Q

Which amino acid needs to be available in high levels to make Pheomelanin

A

Cysteine

87
Q

Cysteine is required for synthesis of which: eumelanin or pheomelanin

A

Pheomelanin

88
Q

Is TYRP1 important for synthesis of eumelanin or pheomelanin?

A

Eumelanin

89
Q

Pigment type switching (eumelanin to pheomelanin, etc) results in _____

A

Agouti coat

90
Q

Agouti protein antagonizes ____ to promote pheomelanin

A

α-MSH

91
Q

MC1R binds α-MSH to promote ______ (melanin type)

A

Eumelanin

92
Q

T or F: animals with oculocutaneous albinism are deaf

A

FALSE
(have melanocytes, they just don’t make melanin. Disorder of melanin synthesis)

93
Q

In addition to hypomelanosis of tissue, which other clinical sign is seen in many cases of oculocutaneous albinism?

A

Nystagmus

94
Q

Which animal has nystagmus 2’ their oculocutaneous albinism?

A

Siamese cats

95
Q

Mutation associated siamese coat (oculocutaneous albinism type 1), recessive

A

Tyrosinase (TYR)

96
Q

Cat breeds with oculocutaneous albinism

A

Siamese
Burmese -> Mocha
Birman
Balinese
Himalayan

97
Q

Oculocutaneous albinism type 2 in Doberman Pinscher gene. “White Doberman”

A

SLC45A2

98
Q

Disease associated with a mutation in SLC45A2 (OCA type 2)

A

White doberman pinscher
Increased risk of melanoma

99
Q

Potential risk factor with white dobermans

A

Increased risk of melanoma

SLC45A2

100
Q

OCA type 1 gene

A

Tyrosinase (affect both eumelanin and pheomelanin)

101
Q

OCA type 2 gene

A

TYRP1 (eumelanin only affected)

102
Q

Which amino acids are crucial in the diet for appropriate pigmentation (2)

A

Phenylalanine
Tyrosine

103
Q

Result of diet deficient in phenylalanine or tyrosine

A

Discoloration of hairs

104
Q

Which element is crucial in the diet for appropriate pigmentation (1)

A

Copper

105
Q

Copper deficient diet results in _____

A

“Ghost eyes” “Spectacle disease”
Graying of periocular hair

Coat greying in puppies

106
Q

“Ghost eyes” etiology

A

diet deficient in copper

107
Q

Epidermal melanin unit

A

1 melanocyte transfering melanosomes to 36 keratinocytes

108
Q

Follicular melanin unit

A

1 melanocyte transfering melanosomes to 5 keratinocytes

109
Q

Dendrites of melanocytes reach as high as ___ in the epidermis

A

Stratum spinosum

110
Q

Proteins at dendrite tip of melanocyte, to transfer melanosome (3)

A

1) Rab27a
2) Melanophilin
3) Myosin-5a

111
Q

Which level of epidermis has the most melanosomes

A

Stratum basale

112
Q

Where does small melanosomes live within a keratinocyte?

A

Perinuclear cap
(microparasol)

113
Q

Where do large melanosomes live within a keratinocyte?

A

Throughout cytoplasm

114
Q

Mechanism that brings small melanosomes to perinuclear cap

A

Melanosome is endocytosed –> dynactin, dynein motor along microtubules to the correct spot

115
Q

Genes implicated in Griscelli syndrome

A

MLPH, Myosin5a, Rab27a

Tips of melanocyte dendrites

116
Q

Lavendar foal syndrome gene

A

Myo5a

117
Q

Histopath from patient w/Lavendar foal syndrome

A

Clumped melanosome in cell bodies of melanocytes

118
Q

Clinical signs Lavendar foal syndrome

A

Dilute coat, neurologic signs, lethal

119
Q

Dog breed with Myo5a disease, GS type-1

A

Mini dachshunds
Dilute coat, neuro signs

120
Q

Gene associated with color dilution alopecia

A

MLPH

D locus

121
Q

Is MLPH mutation alone enough to induce CDA?

A

No. Other modifying factors required

122
Q

Causes for hyperpigmentation (acquired) (3)

A

Solar
Inflammation
Pharmacologic (rubber?)

123
Q

Causes of hypopigmentation by affecting both keratinocytes and melanocytes (acquired)

A

Trauma: burns, wounds, etc.
Disrupt epidermal and follicular melanin units

124
Q

Causes of hypopigmentation by targeting melanocytes (3)

A

-Vitiligo
-Uveodermatologic syndrome (also targets keratinocytes)
-Alopecia areata (also targets keratinocytes)

125
Q

Causes of hypopigmentation by epidermal cytotoxic disorders (4 +3 bonus)

A

-Keratinocyte viral infections
-CLE
-EM
-SJS/TEN

*also vascular/ischemic, CETL, AISBD

126
Q

MITF increases transcription of ___ (4)

A

Tyrosinase
DOPA
TYRP1
TYRP2

127
Q

Main adhesion molecule expressed by melanocytes to connect to the skin.

A

E-cadherin

128
Q

Where are melanocytes in the ear?

A

Cochlea (Stria vascularis)

129
Q

Special stains to visualize melanocytes

A

Fontana Masson, DOPA oxidase reaction, Schmorl’s method

130
Q

Specialized cell for amphibian, fish, reptile, cephalodpod pigmentation

A

Chromatophores

-Reflect light in different ways to determine coloration

131
Q

Cytokines released by melanocytes in inflammation

A

IL-8
IL-1α
TNFα

132
Q

Do melanocytes increase or inhibit keratinocyte proliferation?

A

INHIBIT

133
Q

Major difference between eumelanin and pheomelanin (chemically)

A

Pheomelanin has high sulfur

(yellow, like stinky eggs)

134
Q

Cell signal primarily responsible for regulation of melanogenesis

A

MITF

135
Q

How does UV radiation stimulate melanogenesis?

A

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
Q

POMC is a precursor for α-MSH, which induces melanin synthesis. What else is POMC a precursor for?

A

ACTH

(ACTH can also increase cAMP, leading to more MITF expression/more melanin)

137
Q

What is the agonist of MC1R

A

α-MSH

138
Q

What is the antagonist of MC1R

A

agouti protein

(binds with higher affinity than α-MSH, producing pheomelanin instead)

139
Q

Does α-MSH produce pheomelanin or eumelanin

A

eumelanin

(Agouti is antagonist for MC1R, which switches to pheomelanin)

140
Q

Stimulators of melanogenesis (10)

A

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
Q

Inhibitors of melanogenesis (3)

A

IL-1
IL-6
TNF-α

142
Q

Inhibitor of differentiation from neural crest cells to melanocytes

A

BMP-4

143
Q

Disease from breeding two Overo spotted paint horses (EdnrB)

A

Lethal white foal syndrome

144
Q

Mode of inheritance Lethal white foal syndrome

A

Autosomal recessive

145
Q

Who makes larger melanosomes: follicular or epidermal melanocytes?

A

Follicular

146
Q

Disease of “Blaze” colored ferrets

A

Waardenburg syndrome

Flat skulls, wide set eyes, white stripe on top of head

147
Q

Breed with LYST mutation, Chediak Higashi syndrome

A

Persian cats

148
Q

Breed with lethal lavendar foal syndrome

A

Arabian horses

149
Q

Breeds with hereditary vitiligo

A

Belgian Tervuren dogs
Rottweilers
Old English Sheepdogs

150
Q

Dog breeds with vitiligo (+1 cat, + 1 horse)

A

Rottweiler, Doberman, Collie

Siamese

Arabian horse

151
Q

Cells involved in vitiligo

A

CD8+ T cell attack at melanocytes (Melan-A)

Also NK cells, antibodies (against TYR, TRP1, TRP2)

152
Q

Uveodermatologic target

A

Tyrosinase, TYRP1, TYRP2

Also gp100 in melanocytes

153
Q

Histopath finding vitiligo

A

loss of melanocytes from the epidermis and/or hair follicle. Keratinocytes lack melanosomes
+pigmentary incontinence+ melanophages
+rare: lymphocytes around apoptotic melanocytes

154
Q

3 phases of uveodermatologic syndrome in humans

A

1) Meningoencephalic phase: headaches, seizures, vomit
2) Acute ophthalmic phase: photophobia, eye pain, uveitis, retinal detachment
3) Dermatologic phase: vitiligo, poliosis, alopecia

155
Q

Uveodermatologic syndrome breed

A

Akita

156
Q

Equine leukoderma differentials (10)

A

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
Q

Equine leukotrichia gene

A

Dominant W allele- albino, blano, cremello

158
Q

Potential vitiligo variant in horses

A

Acquired idiopathic leukotrichia, aka “spotted leukotrichia”

Breeds: Thoroughbred, Shire, Arabians

159
Q

Why are melanocytes important for hearing?

A

Melanocytes maintain the K+ potential in endolymph of the cochlea

MITF needed for cochlea development

160
Q

What TF causes follicular melanocytes to proliferate and mature

A

SCF/c-kit

Released by follicular keratinocytes

161
Q

Cause of Congenital Hereditary Sensorineural Deafness in Dalmations

A

Deafness = result of strial degeneration –> absence of strial melnocytes
-Dalmations

Piebald gene
(Also merle gene, but different breeds like Aussies!)

EV ACVD Study (52 decks)

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