2_Regulation of Pigmentation
Transcript of 2_Regulation of Pigmentation
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What determines phenoype?
Oxy/deoxy haemoglobin Carotenoids
Melanin
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What controls Pigmentation?
> 125 distinct genes
- development of melanoblasts
- differentiation & survival melanocytes
> 25 genes
- biogenesis & function of melanosomes / proteins
Critical enzymes include:- Tyrosinase
(tyrosinase related protein -1)- TRP-1
- DCT (DOPAchrometautomerase)
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Critical structural proteins:- Pmel17
- MART 1Structural maturation melanosomes
Mutations: enzymes & structural proteins:
- inherited pigmentary disorders
- eg Albinism:Tyrosinase dysfunction
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Melanocytes
Specialise: in the synthesis of melanin
Derived: melanoblasts
Visible phenotype: Accurate migration, distribution &
functioning Mblasts / Mcyte
Location: - basal layer epidermis
- connected to keratinocytes, fibroblasts
- hair follicle: bulb / ORS
sebaceous gland
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Location of Melanocytes in the Epidermis
keratinocyte
melanocyte
melanin
fibroblast
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SG-Mc
DP
BMc
ORS-Mc
IFD-Mc
E-Mc
Location of Melanocytes in the Hair Follicle
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Melanogenesis
where? melanosomes
3 distinct melanins:
- Eumelanin: Brown/black
- Pheomelanin: Red/yellow
melanosomes mature:
- Transferred cite synthesis = perikaryon dendrites
- neighbouring keratinocytes
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Nucleus
Melanocyte
premelanosome
dendrite
eumelanosomepheomelanosome
Melanocyte structure
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1,4 Benzothiazinyl-alanineLeucoDOPAchromeDHI DOPAchrome
DCT
*
DHICAIndole-5,6-
quinoneIndole-5,6-quinone-
carboxylic acid
DHICA melaninDHI melanin EUMELANIN
Brown/Black
PHEOMELANIN
Yellow/Red
Tyrosinase
L-Tyrosine
Tyrosinase
L-DOPA DOPAquinone CysteinylDOPA+ Cysteine
6BH4 /O2
L-Tyrosine
TRP-1
Melanogenesis
Tyrosinase
Light BrownDark
brown/black
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Why do differences in human skin colour exist?
-Tyrosinase activity
-No. & size of Msomes
-Transfer of mature Msomes Kcytes
Caucasian skin / melanosomes:
- smaller / less melanin
- several Msomes are transferred Kcytes
- Msomes degraded in lower epidermal layers
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Black skin / melanosomes:
- Larger / more melanin
- Msomes transferred individually Kcytes
- Msomes degraded in upper epidermal layers
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M
K
K
K
M
K
K
K
F F F F
Light Dark
UVR UVR
BM
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Constitutive and Facultative Pigmentation
Constitutive: - Genetically determined
- Absence of external influences
Facultative: - pigmentation in response stimuln
- UVR major regulator
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Constitutive Pigmentation
Migration of melanoblasts
Survival & differentiation melanocytes
Expression enzymatic/structural constituents Msomes
Synthesis of eu- pheomelanin
Transport of Msomes dendrites
Transfer Msomes keratinocytes
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Melanocortin -1 Receptor
Major ctrl point in regulating human pigmentation
Regulates quantity & quality of melanins
Agonists MC-1R
-MSH & ACTH (precursor peptide POMC)
Synthesised: Skin cells / Mcytes & Kcytes
Activation MC-1R
- stimulates expression of melanogenic cascade
- synthesis ofeumelanin
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Antagonist MC-1R
Agouti signalling protein (ASP)
- stimulates synthesis of pheomelanin
Mcyte dendricity & proliferation
-MSH & ACTH
expression of MC-1R gene
ProliferationDendricityMelanogenesis
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Mechanism of Action: MC-1R
MC-1R
-MSH/ACTH
CREB
CREMITF
Melanogenesis
MBOX
MITF
Tyrosinase
PKA
cAMPAc
cAMP 2nd messenger system
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What is special about this phenoype?
A. Caused by MC-1R polymorphisms
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MC-1R polymorphisms
Allelic variants / associated with red hair/fair skin
- Arg151Cys, Arg160Trp, Asp294His
Loss of function MC-1R:
- affects -MSH/ACTH binding
- subsequent signalling
Highly associated with:
- poor tanning
- risk of melanoma
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What Causes Tanning?
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Facultative Pigmentation
Regulated by: UVA radiation / tanning reaction
Immediate tanning
- Occurs within mins of exposure & persists for hrs
persistent skin darkening
- Lasts several days
- oxidation and polymerisation of existing melanin
- redistribution of existing melanosomes
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Delayed tanning
- Occurs several days after UVR exposure
- Activation of melanocyte function
- Mcyte proliferation & dendricity
- MITF expression &
Pmel17- downstream melanogenic proteins:
MART-1
Tyrosinase
TRP-1
DCT
Melanogenesis
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EM and EK respond to UV exposure:
- synthesis and secretion of-MSH & ACTH
- expression and function of MC-1R
- Enhances Mcyte responses to -MSH & ACTH
Other melanogenic factors secreted by EK
- SCF (stem cell factor)
- NGF (nerve growth factor)
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Summary
Melanogenesis occurs in melanosomes
Melanin consists of distinct forms:
- Eumelanin: brown/black
- Pheomelanin: yellow/red
Constitutive pigmentation:
- Genetically determined / abs of external influences
Facultative pigmentation:
- pigmentation due to a physiological factor
ratio imp
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References
Yamaguchi Y et al., (2007). The regulation of human skin
pigmentation. The Journal of Biological Chemistry282 (4): 27557-61
Miyamura Y et al., (2006). Regulation of human skin pigmentation
and responses to ultra violet radiation. Pig Cell Res 20: 2-13
Abdel-Malek Z and Kadekaro AL (2007). Human pigmentation: Its
regulation by ultraviolet light and by endocrine and paracrine factors.
Nordlund JJ etal., (Eds.). Oxford University Press, Chapter 20.