BIOLOGYOFMELANOCYTES

Doneby:MohammedAbduljabbar
Done
by: Mohammed Abduljabbar
KAUH

 OBJECTIVES:
Definition & function of Melanocyte
Definition&functionofMelanocyte
Definition&functionofMelanin
E b
EmbryonicdevelopmentofMelanocytes
i d l
t fM l
t
SitespecificMelanocytes
Melanizationsteps
Melanosomes
RegulationofMelanocytefunction
C
Congenitalhypomelanosisdisorders
it l h
l
i di d

 DefinitionMelanocyte:
aredendriticcellslocatedinthebottomlayer(thestratum
y (
basalelayer)ofskinsepidermis.

Othersites:hairfollicles,
eye(uvea)
eye(uvea),
ear(cochlea),
meninges

 Function
Functionofcutaneousmelanocytes:
of cutaneous melanocytes:
istosynthesizemelanininmembranebound
oragnelles called melanosomes & to transfer
oragnellescalledmelanosomes&totransfer
melanosomestoneighboringkeratinocytesto
provide protection from UV irradiation
provideprotectionfromUVirradiation.
Functionofotic,ocular&meningealmelanocytes.

 DefinitionofMelanin:asubstancethatgivescolor
(pigment)tohair,skin,andtheirisoftheeye.Itisproduced
bycellsintheskincalledmelanocytes.

Function:
1) provideprotectionagainstUVinducedDNAdamageby
absorbing&scatteringUVradiation(280400nm)
2)givestheskin,eyes,hairtheircolor
3)importantforproperocularfunction
4)mayprovidesomeprotectiveeffectagainstnoiseinduced
hearingloss

 Factorscausingmelanocytestoincreasemelanin
p
production:
1)UVirradiation(directeffect)
2)Keratinocyte paracrine factors induced by UV
2)KeratinocyteparacrinefactorsinducedbyUV
irradiation

 Normalskincolorisproducedbyfour:(4)skin
pigments.
Epidermis
byexogeneously
by exogeneously producedcarotenoids
produced carotenoids (yellow).
(yellow)
byendogeneously producedmelanin
(brown black yellowred)
(brown,black,yellow
red).
Dermis
byoxygenatedhemoglobin(red)incapillaries
byreducedhemoglobin(blue)invenules.

 Embryonicdevelopmentofmelanocytes:
Melanoblastsmigration&differentiationintomelanocytes
g
y
influencedbyanumbersignalingmoleculesproducedby
neighboringcells,include:
Wnt,
ET3,
BMPs,
SF& cKitligand,
HGF
Cadherins

 Wnt:
1)Directsthematurationofpluripotentneuralcrestcellsinto
)
p p
melanoblasts.
2)InducesthetranscriptionofMITF,MITFaffectsmelanoblast
differentiationbyinducingthetrascriptionofthree
enzymes(tyrosinase,TRP1,TRP2)
HowdoesWntinducethetranscriptionofMITF?

MutationinMITFgeneleadstohypopigmentation disorder
calledWaardenburg syndromeTYPEII&TIETZsyndrome

 BoneMorphogeneticproteins(BMPs)
Endothelins(ETs):
IncludethreemembersET1,ET2,ET3
Include
three members ET1 ET2 ET3
TheybindeitherEdnrAorEdnrBreceptors
ET3 &itsreceptorEdnrB
& its receptor EdnrB receptorareimportantduring
receptor are important during
melanoblastmigration&theirproperexpressionis
required fo survival, prolifration.
requiredfosurvival,prolifration.
DefectinET3oritsreceptorEdnrBleadslossofmelanocytes
Defect
in ET3 or its receptor EdnrB leads loss of melanocytes
WaardenburgsyndromeTYPEIV

 Steelfactor:
isexpressedbyepidermalkeratinocytes&itsreceptorc
is
expressed by epidermal keratinocytes & its receptor cKit
Kitis
is
expressedonmelanoblasts.
BothSF& cKitareimportantinmelanoblastdevelopment&
migration.
g
mutationsofc
mutations
of cKit
KitorSF&leadstomelanoblastfailureto
or SF & leads to melanoblast failure to
migratetotheskinPiebaldism

 Cadherins:
familyoftransmembraneglycoproteins(E,P,N)thatpromote
y
gy p
( ,, )
p
calciumdependentcelltocelladhesion.
ItisthoughtthatcoordinateexpressionofEcadherinsby
epidermalkeratinocytes&melanocytesplaysarolein
suppressingmelanocyteprolifrationintheepidermis.At
times,someepidermalmelanocytesswitchfromE
d
l
l
hf
cadherin toNcadherin &thisswitchallowsthemto
escape the keratinocye mediated growth suppression &
escapethekeratinocyemediatedgrowthsuppression&
prolifrate/aggregateinneststoformnevocellularnevi
HGF:
HGF:
theroleofitinmelanocytedevelopmentstillunclear

 Sitespecificmelanocytes:
Cutaneousmelanocytes:
Cutaneous melanocytes:
Thereisapproximatelyonemelanocyteperfivetosix
keratinocytes
keratinocytes
Melanocytessynthesize&storemelaninincytosolicorganells
Melanocytes
synthesize & store melanin in cytosolic organells
calledmelanosomesthataretransferredtokeratinocytes.

Askeratinocytesarecontinuouslybeingdesquemated,there
isaconstantneedforsynthesis&transferofmelanosomes
frommelanocytestokeratinocytestomaintaincutaneous
pigmentation
i
i

Melanocytedensity/squaremmrangesfrom550to1200,
withthehighestconcentrationwithinface&genetalia
i h h hi h
i
i hi f
&
li

Melanocytedensityisalmostthesameinallindividualsof
differentethnicbackground&thuscutaneous
pigmentationdoesntdependonmelanocytenumber.
Q itdependsonwhat?
1)Melanogenicactivitywithinthemelanocyte
2)Theproportionofmaturemelanosomes
3)Typeofmelanin(eumelanin,orpheomelanin)
4)melanosomestransfer&distributionwithinthe
keratinocytes
5)Sizeofmelanosomes

 Hairfolliclemelanocytes:
Incontrasttointerfollicularmelanocytes,thefollicular
melanin unit undergoes cyclic modifications in coordination
melaninunitundergoescyclicmodificationsincoordination
withhaircycle

Haircolorisdeterminedbyamountofmelanintransferredto
Hair
color is determined by amount of melanin transferred to
keratinocytesformingthehairshaftaswellasbytheratio
ofeumelanin(blackbrown)topheomelanin

 Ocularmelanocytes:
Unlikecutaneousmelanocytes,ocularmelanocytesarein
contact only with each other & dontttransfer
contactonlywitheachother&don
transfer
melanosomes.
Qwhatarethefunctionsofmelaninintheeye?
Albinos mayhavevisualabnormalitisduetoabsenceof
melanin

 Oticmelanocytes:
Resideincochlea&areimportantforhearing,aslossofotic
melanocytes may leads to deafness as in Waardenburg
melanocytesmayleadstodeafnessasinWaardenburg
syndromeTYPEII.
QWhataboutalbinos?Aretheydeaf?
y
ANo

Cephalicmelanocytes

 Melanosome:
Ismembraneboundorganelleinwhichmelanin
biosynthesis & storage take place
biosynthesis&storagetakeplace
Anddependingonthetypeofmelanin(eumelaninor
And
depending on the type of melanin(eumelanin or
pheomelanin)synthesized,melanosomescanbedivided
intoeumelanosome&pheomelanosome

 Synthesis&distributionofmelaninintheepidermis
p
involvesseveralsteps:
1)Transcriptionofproteinsrequiredformelaninsynthesis
)
g
2)Melanosomebiogenesis
3)Sortingofmelanogenicproteinsintomelanosomesto
initiatemelaninsynthesiswithinthemelanosome
y
4)Transportofthematuremelanosomestothetipsof
melanocytedendrites
5)Transferofmelanosomestokeratinocytes

 Melanosomebiogenesis:
Display4maturationstages
p y
g :

Stage1 melanosomesdevelopfromtheendoplasmic
reticulum&theyhaveamorphousmatrix

Stage2
both(eumelanosomes&pheomelanosomeshave
organizedstructuredfibrillar(threadlike)matrixbut
stage2 pheomelanosomes: melaninsynthesisalready
takesplace,while
stage2eumelanosomes:noactivemelaninsynthesis

Stage3
stage3 pheomelanosomes: continuationof
melaninsynthesis&deposition
stage3 eumelanosomes: activemelaninsynthesis
&depositionstartsinthisstage

Stage4
Bothpheomelanosomes&eumelanosomesarefully
melanized

 Melanogenicproteins:
Importantformelaninsynthesis&melanosomesmaturation
1)enzymes(tyrosinase TRP1 TRP2 protein kinase cbeta)
1)enzymes(tyrosinase,TRP1,TRP2,proteinkinasecbeta)
2)Structuralproteins(Pmel17,MART1)
3)Additional melanogenic proteins
3)Additionalmelanogenicproteins
(PProtein,HeterotetramericadaptorproteincomlexesAps)
4)
4)regulatoryproteins(Mitf,Melanocortin1receptor)
l t
t i (Mitf M l
ti 1
t )

1)enzymes:
Tyrosinase:
: isthekeyenzymeformelaninsynthesis.
is the key enzyme for melanin synthesis.
withinthemelanosome,tyrosinasespansthemelanosomal
outer membrane.It has three domains: inner melanosomal
outermembrane.Ithasthreedomains:innermelanosomal
domain(form90%oftheprotein),amelanosomal
transmembranedomain,andacytoplasmic
domain.Histadineresiduespresentintheinnerdomain
bindcopperionswhicharerequiredfortyrosinaseactivity.

Inadditiontothat,twoserineresiduesonthe
In
addition to that,two serine residues on the
cytoplasmicdomainmustbephospholyratedby
protein kinase Cbeta
proteinkinaseC
betatoactivatetyrosinase,inthe
to activate tyrosinase, in the
absenceofthisphosphorylation,pigmentationdoes
not occure.
notoccure.

MutationoftyrosinasefoundinOCAtype1.

Tyrosinaserelatedprotein1(TRP1)
Importance:
p
Playsaroleintyrosinaseactivationandstabilization
Increasesratioofeumelanintopheomelanin
Increases ratio of eumelanin to pheomelanin
Playsaroleinmelanosomalbiogenesis
Absence of TRP1
AbsenceofTRP
1resultsinthepigmentarydisorder
results in the pigmentary disorder
OCAtype3

Tyrosinase related protein 2 (TRP 2)

Tyrosinaserelatedprotein2(TRP2)
Involvedinmelaninbiosynthesis,convertingDOPAchrometo
DHICA melanin (brown)
DHICAmelanin(brown)

ProteinkinaseCbeta

2)Structuralproteins(Pmel17&MART1)
Both are important for proper deposition of melanin
Bothareimportantforproperdepositionofmelanin
withinthemelanosomes.
Upto date nohaypopigmentarydisordersassociated
Uptodate,
no haypopigmentary disorders associated
withnonfunctioningMART1orPmel17havebeen
identified

3)Additionalmelanogenicproteins
P Protein
PProtein
ProposedFunctions:
Maintainsacidicenviromentwithinthemelanosomes
Maintains acidic enviroment within the melanosomes
Transportingtyrosinaseintothemelanosomes
Individuals lacking P Protein display OCA type 2 largely due
IndividualslackingPProteindisplayOCAtype2,largelydue
toimpropermelanosomalPH.

Heterotetramericadaptorproteincomplexes(Aps)
AP3&possiblyAP1facilitatetyrosinasetransportfrom
p
y
y
p
endosomestomelanosomes.
IndividualswithdefectsinAP3 display
HermanskyPudlaksyndrome2(OCA+plateletsdysfunction+
pulmonarydisease)

4)Regulatoryproteins:
Microphthalmiaassociated
Microphthalmia
associatedtranscriptionfactor
transcription factor
Mitfgeneisthemastergeneformelanocytesurvival&isa
key factor regulating the transcription of the major
keyfactorregulatingthetranscriptionofthemajor
melanogenicproteins(tyrosinase,TRP1,TRP2,PKCbeta
&MART1)
MutationsinMitffoundinthepigmentarydisorders
waardenburgsyndrometype2&tietzsyndrome.
Mitfexpressionisunderthecontrolofseveraltranscription
factorsincludingSox10&Pax3.
Sox10(ismutatedinWStype4)
Pax3(ismutatedinWStype3&1)

Melanocortin1receptor(MC1R)
ACTH &MSH
& MSH activateMC1R&stimulate
activate MC1R & stimulate
melanogenesis(eumelaninoverpheomelanin).
Thatsswhypatientswithaddisondisease&nelson
That
why patients with addison disease & nelson
syndrome havegeneralizedskin
hyperpigmentation.

 Melaninbiosynthesis:
Site:melanocytes(melanosomes)
Types:
E
Eumelanin(brown,black)
l i (b
bl k)
Pheomelanin(redyellow)

Themainfunctionofmelanin:
Protection against UV induced DNA damage.
ProtectionagainstUVinducedDNAdamage.
Qwhyislightskinnedredhairedindividualsaremore
prone to UV induced melanoma?
pronetoUVinducedmelanoma?

 Melanocytedendrites:
Are branching processes that interact with
Arebranchingprocessesthatinteractwith
keratinocytes
The major structural component of melanocyte
Themajorstructuralcomponentofmelanocyte
dendritesisactin
Q h td
Qwhatdoesincreasemelanocytedendricity?
i
l
t d d i it ?
UVirradiation
keratinocytederivedfactors(ET1,nervegrowth
factor,ACTH,MSH,PGE2,PGF2)

 Melanosomaltransport:
Within melanocytes: melanosomes: melanosomesare
Withinmelanocytes:melanosomes:
melanosomes are
transferredfromthemelanocyteperikaryontothetipsof
melanocytesdendrites.Melanosomestransporttakesplace
onmicrotubulethatarearrangedparalleltothelongaxisof
thedendrite.thetransportiscontrolledby2classesof
microtubulesattachedmotorproteinskinesins
i
b l
h d
i ki i &
&
dyneins.bothmotorproteinsactasashortcrossbridge
structures connecting the melanosome to the
structuresconnectingthemelanosometothe
microtubules.
Centrifugal(away from the center)movement is mediated by
Centrifugal(awayfromthecenter)movementismediatedby
kinesin,whereasCentripetal(inwardtothe
center)movementismediatedbydynein

Melanosomeswithnetcentrifugalmovement,the
melanosome will end with binding Myo5a
melanosomewillendwithbindingMyo5a.
WhatisRab27a?
Whatismelanophilin?
Myosin5abindsRab27,Rab27bindsmelanophilin,
melanophilinbindsmelanosome

Mutationsofanyofthepreviousgene
p
products(Myo5a,Rab27a,melanophilin)resultin
( y
p
)
decreasecutaneouspigmentationleadingto
y
Griscellisyndrome.
Myo5a alsoexpressedinthebrain,somutationsof
this gene may also cause neurological
thisgenemayalsocauseneurological
abnormalities.
Rab27a playsaroleinimmunoregulation&
plays a role in immunoregulation &
individualswithmutationsofthisgenedisplay
abnormalities in the immune system
abnormalitiesintheimmunesystem

Tokeratinocytes:
1)Exocytosis:fusionofthemelanosomalmembranewiththe
)
y
melanocyteplasmamembrane,melanosomeisreleasedto
theintercellularspaceandphagocytosisbysurrounding
keratinocytesoccure
2)Cytophagocytosis:keratinocytescytophagocytosethetipof
amelanocytedendrite
l
d d
3)Fusionofmelanocyte&keratinocyteplasmamembrane
createaspacethroughwhichmelanosomesaretransferred
t
th
h hi h
l
t
f
d
4)Sheddingofmelanosomefilledvesiclesfollowedby
phagocytosis of the vesicles by keratinocytes
phagocytosisofthevesiclesbykeratinocytes

Regulationofmelanocyte function:
UVirradiationcandirectlystimulatemelanocyte dendricity &melanin
p
productionorindirectlybystimulatingproductionofkeratinocytes
y y
gp
y
derivedfactorswhichincreasemelanocyte dendricity &melanin
production

 Congenitalhypomelanosisdisorders
Ariseduetodefectin:
1)Melanocyte embryonic development
1)Melanocyteembryonicdevelopment
WS14,Tietzsyndrome,Piebaldism
2)Disorder of melanin synthesis
2)Disorderofmelaninsynthesis
OCA14
3)M l
3)Melanosomeformation,
f
ti
t
transport&transfer
t&t
f
HPS,ChediakHigashisyndrome,Gracellisyndrome

1)Melanocyteembryonicdevelopment
(Disorder)
(Disorder)(affectedprotein)
(affected protein)
WS1
PAX3
WS2
Mitf
PAX3
WS3
WS4
Sox10,ET3&EDNRB
Piebaldism
SF or cKit
SForc
Kit
Tietzsyndrome
Mitf

2)Disorderofmelaninsynthesis
(Disorder)
(Disorder)(affectedprotein)
(affected protein)
tyrosinase
OCA1
PProtein
OCA2
TRP1
OCA3
MATP
OCA4

3)Melanosomeformation,transport&transfer
(Disorder)
(Disorder)(affectedprotein)
(affected protein)
Myo5a,Rab27a
Gricellisyndrome
Melanophilin
Ch di k hi hi
Chediakhigashi
LYST
syndrome