the regulation of skin pigmentation
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TheRegulationofSkinPigmentation
MelanogenesisoccursinmelanosomesMelaninconsistsofdistinctforms:-Eumelanin:brown/black-Pheomelanin:yellow/redratioimp
Constitutivepigmentation:-Geneticallydetermined/absofexternalinfluencesFacultativepigmentation:
- pigmentationduetoaphysiologicalfactor
Regulationofconstitutivepigmentation/MC-1R
Regulationoffacultativepigmentation/UVR
Whatdeterminesphenoype?Oxy/deoxyhaemoglobinCarotenoids
MelaninWhatcontrolsPigmentation?
>125distinctgenes
-developmentofmelanoblasts-differentiation&survivalmelanocytes
>25genes-biogenesis&functionofmelanosomes/proteinsMelanosomes,whicharecloselyrelatedtolysosomesandarewithinthefamilyoflysosome-relatedorganelles(LROs),requireanumberofspecificenzymaticandstructuralproteinstomatureandbecome
competenttoproducemelaninCriticalenzymesinclude:
1. Tyrosinase2. TYRP-1(tyrosinaserelatedprotein-1)3. DCT(DOPAchrometautomerase)
Criticalstructuralproteins:1-Pmel172-MART1forstructuralmaturationmelanosomes
Mutations:enzymes&structuralproteins:-inheritedpigmentarydisordersegAlbinism:Tyrosinasedysfunction
MelanocytesSpecialise:inthesynthesisofmelaninDerived:melanoblastsVisiblephenotype:Accuratemigration,distribution&functioningMblasts/McyteLocation:-basallayerepidermis-connectedtokeratinocytes,fibroblasts
-hairfollicle:bulb/ORSsebaceousgland-eye,innerear
Melanogenesiswhere?melanosomes
3distinctmelanins:- Eumelanin:darkandblackhair
o DHImelanin-darkbrown/blackinsolublemelanino DHICA-melanin-lighterbrowncolor,moderatelysolubleandofintermediatesize
Pheomelanin:Red/freckledhair--yellow-redsolublemelanin
melanosomesmature:-Transferredcitesynthesis=perikaryondendrites-neighbouringkeratinocytes
Melanocytestructure
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whydodifferencesinhumanskincolourexist?- Tyrosinaseactivity-- No.&sizeofMsomes- TransferofmatureMsomesKcytes- MC:KC1:10- MCcontributemelaninto40KC-
Caucasianskin/melanosomes:
-smaller/lessmelanin-severalMsomesaretransferredKcytes
-Msomesdegradedinlowerepidermallayers
Blackskin/melanosomes:-Larger/moremelanin
-MsomestransferredindividuallyKcytes
-MsomesdegradedinupperepidermallayersConstitutiveandFacultativePigmentation
Constitutive:-Geneticallydetermined-Absenceofexternal
influences
Facultative:-pigmentationinresponsestimulation
-UVRmajorregulatorConstitutivePigmentation
DevelopmentalConsiderations(EMI)refertoproximateparacrineorjuxtacrinecross-talkbetweenstromalfibroblastsandtissueepithelia(EMT),whichrefertothetransdifferentiationofepithelialcellstoafibroblast-likephenotype.EMIaswellasEMTisrequiredforthedevelopmentofvariousorgans;thekeysignalingpathways
involvedinEMIincludehomeobox(HOX),fibroblastgrowthfactors,sonichedgehogs,Wnt/B-catenin/Lef1,andbonemorphogenesisproteins.
Determinationfactors
Migrationofmelanoblasts Survival&differentiationmelanocytes Expressionenzymatic/structuralconstituentsMsomes Synthesisofeuandpheomelanin TransportofMsomesdendrites TransferMsomeskeratinocytes Distributionofmelanininsuprabasallayersoftheskin
Melanocortin-1Receptor-GPCRMajorctrlpointinregulatinghumanpigmentationRegulatesquantity&qualityofmelanins
AgonistsMC-1R
-MSH&ACTH(precursorpeptidePOMC)Synthesised:Skincells/Mcytes&KcytesActivationMC-1R
- stimulatesexpressionofmelanogeniccascade-synthesisofeumelanin-MSH&ACTH
Mcytedendricity&proliferationexpressionofMC-1Rgene
MelanogenesisDendricityproliferation
AntagonistMC-1R
Agoutisignallingprotein(ASP)-stimulatessynthesisofpheomelanin
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MC-1Rpolymorphisms
RedhairandfairskinAllelicvariants/associatedwithredhair/fairskin-Arg151Cys,Arg160Trp,Asp294His
LossoffunctionMC-1R:-affects-MSH/ACTHbinding-subsequentsignallingHighlyassociatedwith:-poortanning
-riskofmelanoma
FacultativePigmentation
Regulatedby:UVAradiation/tanningreaction
Immediatetanning
-Occurswithinminsofexposure&persistsforhrspersistentskindarkening
-Lastsseveraldays
-oxidationandpolymerisationofexistingmelanin-redistributionofexistingmelanosomes
Delayedtanning
-OccursseveraldaysafterUVRexposure-Activationofmelanocytefunction-Mcyteproliferation&dendricity
-MITFexpression&
-downstreammelanogenicproteins:Pmel17 MART-1 Tyrosinase TRP-1 DCT increasedMelanogenesis
-Increased levels of PAR2 in keratinocytes which increases uptake and distribution of melanosomes
EMandEKrespondtoUVexposure:
- synthesisandsecretionof-MSH&ACTHexpressionandfunctionofMC-1REnhancesMcyteresponsesto-MSH&ACTH
MK
ET-1MC1R+EDNRB(EM) IL-1ACTH, MSH, endothelin 1, and bFGF SCF(stemcellfactor) NGF(nervegrowthfactor)preventsmelanocyteapoptoticcelldeathfollowingUVexposure Stimulationofp53increasesexpressionofthePOMCgene,leadingtoincreasedsecretionof
MSHandstimulationofMC1Rfunctioninneighboringmelanocytes
Fibroblastsgrowth factors -HGF, bFGF, and SCF, all factors that stimulate pigmentation via their
receptors on melanocytes
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Regulation of human skin pigmentation and responses to ultraviolet radiation
Pigmentationofhumanskiniscloselyinvolvedinprotectionagainstenvironmentalstresses,inpartic-ularexposuretoultraviolet(UV)radiation.Itiswellknownthatdarkerskinissignificantlymoreresist-
anttothedamagingeffectsofUV,suchasphoto-carcinogenesisandphotoaging,thanislighterskin.Constitutiveskinpigmentationdependsontheamountofmelaninanditsdistributioninthattis-sue.
MelaninissignificantlyphotoprotectiveandepidermalcellsindarkerskinincurlessDNAdam-agethandothoseinlighterskin.ThisreviewsummarizescurrentunderstandingoftheregulationofconstitutivehumanskinpigmentationandresponsestoUVradiation,withemphasisonphysiologicalfactorsthatinfluencethoseprocesses.Furtherresearchisneededtocharacterizetheroleofskinpigmentationtoreducephotocarcinogenesisandtodevelopeffectivestrategiestominimizesuchrisks.-Melanocytedensityisalmostidenticalinskinofdifferentcolorsandracialorigins-Constitutiveskinpigmentationdependsprimarilyontheamountofmelaninpresentandonitsdistribution.-Melaninmostcertainlyisphotoprotectivetoasignificantdegree
darkerskinincursignificantlylessDNAdamagethaninlighterskin.Interestingly,melanogenicactivitiesincreasemoreefficientlyindarkerskinthaninlighterskinexposedtocomparabledosesofUV.melanogenicproteins
- thetranscriptionfactorMITFrespondsmostquicklytoUV(within12days).- tyrosinase,Tyrp1,Pmel17,andDCTisslower(c.1week)- increasesinmelaninsynthesistakeabitlonger(c.3weeks)- increasesinmelano-cytedensitytakeeenlonger(45weeks).
Thedistributionofmelaninintheskinplaysanimportantroleinvisiblepigmentationandnodoubtinphoto-protectivecapacity.Although,thereisaninitialsurge(1week)intheupwardmigrationofexistingpigmenttowardsthesurfaceoftheepidermis,thebalanceinpigmentdistributionisrestoredby45weekswhennewsynthesisofmelaninhasbeenestablished.Itisclearthatrelativelysmallchangesin
melanincontentand/ordistributioncanmakerelativelylargechangesinvisiblepigmentation.Thoseaffectnotonlyconstitutivepigmentationthatdefinesracial/ethnicdifferencesbutalsoresponsestoUVexposure.
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