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Regulation of Skin Pigmentation Melanogenesis occurs in melanosomes Melanin consists of distinct forms: - Eumelanin: brown/black - Pheomelanin: yellow/red ratio imp Constitutive pigmentation: - Genetically determined / abs of external influences Facultative pigmentation: - pigmentation due to a physiological factor Regulation of constitutive pigmentation / MC-1R Regulation of facultative pigmentation / UVR What determines phenoype? Oxy/deoxy haemoglobin Carotenoids Melanin What controls Pigmentation? > 125 distinct genes - development of melanoblasts - differentiation & survival melanocytes > 25 genes - biogenesis & function of melanosomes / proteins Melanosomes, which are closely related to lysosomes and are within the family of lysosome-related organelles (LROs),require a number of specific enzymatic and structural proteins to mature and become competent to produce melanin Critical enzymes include: 1. Tyrosinase 2. TYRP-1 (tyrosinase related protein -1) 3. DCT (DOPAchrometautomerase) Critical structural proteins: 1- Pmel17 2- MART1 for structural maturation melanosomes Mutations: enzymes & structural proteins: - inherited pigmentary disorders eg Albinism:Tyrosinase dysfunction 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 - eye, inner ear Melanogenesis where? melanosomes 3 distinct melanins: - Eumelanin: dark and black hair o DHI melanin -dark brown /black insoluble melanin o DHICA-melanin -lighter brown color, moderately soluble and of intermediate size Pheomelanin: Red/freckled hair--yellow-red soluble melanin melanosomes mature: - Transferred cite synthesis = perikaryon dendrites - neighbouring keratinocytes Melanocyte structure

 why do differences in human skin colour exist? - Tyrosinase activity - - No. & size of Msomes - Transfer of mature Msomes Kcytes - MC:KC1:10 - MC contribute melanin to 40 KC - Caucasian skin / melanosomes: - smaller / less melanin - several Msomes are transferred Kcytes - Msomes degraded in lower epidermal layers Black skin / melanosomes: - Larger / more melanin - Msomes transferred individually Kcytes - Msomes degraded in upper epidermal layers Constitutive and Facultative Pigmentation Constitutive: - Genetically determined - Absence of external influences Facultative: - pigmentation in response stimulation - UVR major regulator Constitutive Pigmentation Developmental Considerations (EMI) refer to proximate paracrine or juxtacrine cross-talk between stromal fibroblasts and tissue epithelia (EMT), which refer to the transdifferentiation of epithelial cells to a fibroblast-like phenotype. EMI as well as EMT is required for the development of various organs; the key signaling pathways involved in EMI include homeobox (HOX), fibroblast growth factors, sonic hedgehogs, Wnt/B- catenin/Lef1, and bone morphogenesis proteins. Determination factors Migration of melanoblasts Survival & differentiation melanocytes Expression enzymatic/structural constituents Msomes Synthesis of eu and pheomelanin Transport of Msomes dendrites Transfer Msomes keratinocytes Distribution of melanin in suprabasal layers of the skin Melanocortin -1 Receptor-GPCR 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 of eumelanin -MSH & ACTH Mcyte dendricity & proliferation expression of MC-1R gene Melanogenesis Dendricityproliferation Antagonist MC-1R Agouti signalling protein (ASP) - stimulates synthesis of pheomelanin

MC-1R polymorphisms Red hair and fair skin 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 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 Delayed tanning - Occurs several days after UVR exposure - Activation of melanocyte function - Mcyte proliferation & dendricity - MITF expression & - downstream melanogenic proteins: Pmel17 MART-1 Tyrosinase TRP-1 DCT increased Melanogenesis

-Increased levels of PAR2 in keratinocytes which increases uptake and distribution of melanosomes
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 MK ET-1 MC1R + EDNRB (EM) IL-1 ACTH, MSH, endothelin 1, and bFGF SCF (stem cell factor) NGF (nerve growth factor) prevents melanocyte apoptotic cell death following UV exposure Stimulation of p53increases expression of the POMC gene, leading to increased secretion of MSH and stimulation of MC1R function in neighboring melanocytes Fibroblasts growth factors -HGF, bFGF, and SCF, all factors that stimulate pigmentation via their

receptors on melanocytes

Regulation of human skin pigmentation and responses to ultraviolet radiation

Pigmentation of human skin is closely involved in protection against environmental stresses, in partic- ular exposure to ultraviolet (UV) radiation. It is well known that darker skin is significantly more resist- ant to the damaging effects of UV, such as photo- carcinogenesis and photoaging, than is lighter skin. Constitutive skin pigmentation depends on the amount of melanin and its distribution in that tis- sue. Melanin is significantly photoprotective and epidermal cells in darker skin incur less DNA dam- age than do those in lighter skin. This review summarizes current understanding of the regulation of constitutive human skin pigmentation and responses to UV radiation, with emphasis on physiological factors that influence those processes. Further research is needed to characterize the role of skin pigmentation to reduce photocarcinogenesis and to develop effective strategies to minimize such risks. -Melanocyte density is almost identical in skin of different colors and racial origins -Constitutive skin pigmentation depends primarily on the amount of melanin present and on its distribution. -Melanin most certainly is photoprotective to a significant degree darker skin incur significantly less DNA damage than in lighter skin. Interestingly, melanogenic activities increase more efficiently in darker skin than in lighter skin exposed to comparable doses of UV. melanogenic proteins - the transcription factor MITF responds most quickly to UV (within 12 days). - tyrosinase, Tyrp1, Pmel17, and DCT is slower (c.1 week) - increases in melanin synthesis take a bit longer (c.3 weeks) - increases in melano- cyte density take een longer (45 weeks). The distribution of melanin in the skin plays an important role in visible pigmentation and no doubt in photo- protective capacity. Although, there is an initial surge (1 week) in the upward migration of existing pigment towards the surface of the epidermis, the balance in pigment distribution is restored by 45 weeks when new synthesis of melanin has been established. It is clear that relatively small changes in melanin content and/or distribution can make relatively large changes in visible pigmentation. Those affect not only constitutive pigmentation that defines racial/ethnic differences but also responses to UV exposure.