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

2020

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.

2_regulation of pigmentation

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