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MELANOCYTE

&
MELANOGENESIS
DR IMTIAZ BASHA
MD DVL
NORMAL SKIN COLOUR
 Major determinant of skin colour is MELANIN
 Racial&Ethnic differences in skin colour are
related to number ,size, shape,
distribution,packaging and degradation of
melanin-laden organelles called Melanosomes
 Dark skinned

people have
numerous,large,heavily melanised,distributed
as solitary unit,slowly degrading melanosomes
in keratinocytes ,&have larger ,highly dendritic
melanocytes &vice versa.
 Melanosomes are produced by melanocytes
TYPES OF MELANIN
PIGMENTATION
 Constitutive:Genetically
determined melanin
pigmentation in the
absence of sun exposure
and other influences
 Facultative(inducible):
Pigmentation result
from sun exposure
 Other:Hormonal effect
REGIONAL VARIATION OF
SKIN COLOUR
Due to variation in melanocyte
population in different regions of
human body variable pigmentation
is seen .
Total epidermal melanocyte
population:2×10 9
Face & genital area has greater
density of melanocytes than in trunk
(range 2900±249 in face to
1100±215 in upper arm)
Reduction in number &
activity of melanocytes
occurs with ageing i.e
6-8%per decade,more of
follicular melanocytes &
spared eidermal melanocytes from sun
exposure are declined leading to
graying of hair & lightening of skin
colour
EMBRYOLOGY OF MELANOCYTE

 Origin of melanocyte is from neural crest


cells Exception melanocyte in retina are
derived from optic cup
 Primitive melanocytes:8th wk gestation
 Melanosome showing early
melanization:10th wk gestation
 Fetal skin contain melanocytes
basally,suprabasally
 Neonatal skin contain melanocytes only
basally
 1:36 ratio of melanocyte:keratynocyte
form the one Epidermal melanin unit
VARIOUS TISSUES
CONTAINING MELANOCYTES
EPIDERMIS
VARIOUS EPITHELIA OF MUCOUS
MEMBRANE
HAIR FOLLICLES--- BULB
DERMIS
LEPTOMENINGES
INNER EAR---COCHLEA
RETINA,CHOROID,IRIS,OPTIC NERVE
AROUND BLOOD VESSELS
PERIPHERAL NERVES,SYMPATHETIC CHAIN
LINNING COELOMIC CAVITY
STRUCTURE OF MELANOCYTE
MELANOCYTE
ULTRA STRUCTURE OF
MELNOCYTE
2 Types of melanocytes:SECRETORY,
NON-SECRETORY
 Secretory melanocytes present in
basal layer of epidermis form
network of dendrites in the basal
layer
 They act as unicellular glands
producing melanosomes that are
transferred to surrounding epidermal
keratinocytes –cytocrine activity
 Non-Secretory melanocytes called
MELANOPHORES do not transfer
melanosome but redistribute them from
perinucular zone into dendrites and back
again
 Electron microscopy:Melanocyte contain
numerous mitocondria well-developed
RER,prominent Golgi
apparatus,cytoplasmic filaments
 Main distinguishing feature of melanocyte
from keratinocyte : Absence of
DESMOSOMES and TONOFILAMENTES in
melanocyte
SYNTHESIS OF
ENZYMES,PROTEINS FOR
MELANIN FORMATON
GLYCOSYLATION:TYROSINASE,TRP-
1,TRP-2 OCCURS IN ER
FOLDING OF THESE PROTEINS IN ER
MATURATION OF PROTEINS IN GOLGI
APPARATUS AND ENDOSOMES
FINALLY SORTING OF PROTEINS INTO
MELANOSOMES
OVERVIEW OF
MELANOGENESIS
MELANIZATION
TRANSCRITION OF PROTEINS FOR
MELANOGENESIS
MELANOSOME BIOGENESIS
SORTING OF MELANOGENIC
PROTEINS INTO MELANOSOMES
TRANSPORT OF MELANOSOMES TO
MELANOCYTE DENDRITES
TRANSFER OF MELANOSOMES TO
KERATINOCTES
MELANOSOMES
STAGES OF MELANOSOMES
STAGE 1 : spherical,membrane bound
vesicles with highly organised internal
structure composed of logitudinally
oriented concentric lamellae –
melanofilaments .with distinctive
periodicity of 9nm,this vesicle possess
tyrosinase activity .
Tyrosinase is produced on membrane-
bound ribosomes and transferred via ER to
golgi where it accumulates in vesicles.
Stage 2 :Melanosomes are oval
contain numerous melanofilamentes
with or without cross-linking with
little organisation.
Melanin deposition first begins in this
stage in case of pheomelanosomes
but not in eumelanosomes
Stage 3: Internal structure of
melanosomes is partially obscured
by deposition of melanin
stage 4 :mature melanosome
appears electron dense.
 Between eletron dense melanised
core and outer membranes,mature
melanosomes house distinct
vesicles,40nm, VESICULOGLOBULAR
BODIES
These are involved in organization of
melanosomes and are found both in
eumelanosomes and
pheomelanosomes.
 They play key role in development of
macromolanosomes
TRANSPORT OF
MELANOSOMES
 Active transport :
 formation of melanocyte dendrites
 projection of dendrites into
keratinocyte cytoplasm
 Pinching of tip of dendrite
 Phagocytosis of melanosomes by
keratinocyte
MELANOSOME TRANPORT ACROSS
MELANOCYTE DENDRITE
Melanosomes moves bidirectionally along
dendrite

Attach to microtubule through motor


protein
kinesin(antegrade),dynein(retrograde)

At the tip they are captured in actin


filament

Myosin-va mediate binding of melanosome


to actin through linker protein Rab27
,melanophilin
TRANSFER TO KERATINOCYTE
4 Pathways of transport :
 EXOCYTOSIS
 CYTOPHAGOCYTOSIS
 FUSIONOF KERATINOCYTE AND
MELANOCYTE MEMBRANE
 TRANSFER BY MEMBRANE VESICLE
• Nonexposed skin of Caucasoids,
especially those with light skin, such
transferred melanosomes are found
almost exclusively in the basal cell
layer and, to a slight degree, in the
layer of keratinocytes above the
basal cell layer. However, in African
Americans, in whom melanosomes
are also principally seen in the basal
cell layer, moderate quantities of
melanosomes are found throughout
the epidermis, including the stratum
corneum (66).
ENZYME ACTIVITY IN
MELANOSOMES
 During progression from stage to 4
melanosomes
 Tyrosinase decreases
 Acid phosphotase increases
 Other enzymes adenosine
triphophotase,hydrolase.
 Acid phosphotase,hydrolase are
thought to regulate degradation or
transfer of melanosomes.
 EUMELANINS  PHEOMELANINS
 BLACK OR BROWN  YELLOWISH TO
 INSOLUBLE IN ALL REDDISH BROWN
SOLVENTS  ALKALI SOLUBLE
 NITROGENOUS PIGMENT
 CONTAIN SULPHUR IN
ADDITION TO NITROGEN
 OXIDATIVE
 OXIDATIVE
POLYMERISATION OF POLYMERISATION OF
5-6DIHROXYINDOLE CYSTINE-S-YI-DOPA VIA
DERIVED FROM 1-4BENZOTHIAZINE
TYROSIN INTERMEDIATES
MANUFACTURED IN  MANUFACTURED IN
ELLIPSOIDAL SPHERICAL
MELANOSOMES
MELANOSOMES
 FEMALES >MALE
 lips, nipples, glans
of the penis, and
vagina
 IS CARCINOGENIC
Melanin synthesis
 STIMULATORS:
 MSH
 ACTH
 LIPOTROPINS
 ESTROGEN
 PROGESTERON
 THYROXIN
 ANDROGEN
 ARACHIDONIC ACID,OLEIC
ACID,PROSTAGLANDINSE 2,
SIGNALING PATHWAYS REGULATING
MELANOGENESIS
 UV RAYS ---- Α-MSH/ACTH --MCIR --ADENYLATE
CYCLASE - CAMP PKA -GENE TRANSCRIPTION

 STEEL FACTOR -- BINDING TO C-Kit --PHOSPHORYLATE


RECEPTOR ---ACTIVATION MITOGEN-ACTIVATED
PROTEIN(MAP) ---- Mitf - p (MICROPHTHALMIA-
ASSOCIATED TRANSCRIPTION FACTOR)-----------
TRANSCRIPTION OF TYROSINASE,TRP-1,TRP-2

 UVRAYS----DAG RELEASE-PKC-ß-PHOSPHORYLATE
TYROSINASE

 NO--GUANYLATE CYCLASE---CGMP --TYROSINASE

 UV RAYS BONE MORPHO GENETIC PROTEIN (BMP)


RECEPTORS PREVENTS BMP -4 MEDIATED INHIBITION ON
MELANONOGENES
MELANIN BIOSYNTHASIS
 Synthesis of both pigments involves rate limiting
step –oxidation of tyrosin to L-DOPA by
(RAPER-MANSON STEP)TYROSINASE/TYROSINE
OXIDASE/DOPA OXIDASE/MONOPHENOL/DOPA-
OXYGFEN OXIDOREDUCTASE
 LDOPA AFFINITY OF TYROSINASE TO BOTH
TYROSINE AND L-DOPA(3,4 DIHYDROXY
PHENYLALANIN)
 DOPA --DOPAQUINONE(OXIDATION BY
TYROSINASE)
 TILL NOW PATHWAY ISSAME FOR BOTH PIGMENTS
EUMELANIN
Raper–Mason scheme, dopaquinone undergoes cyclization
to cyclodopa (leukodopachrome), which is rapidly oxidized
to dopachrome [9,10].

Dopachrome then becomes rearranged


to form 5,6-dihydroxyindole (Di) or, in smaller
amounts, 5,6-dihydroxyindole-2-carboxylic acid (DiCA).

 It was proposed that 5,6-indolequinone then polymerized


to form EUMELANINS

 Metals such as copper, zinc and iron, are found in high


levels in pigmented tissues

The ratio of DiCA to Di determines the extent to


which these intermediates take part in the
subsequent polymerization process to form
eumelanins.
PHEOMELANINS
 Addition of the SH group of cysteine
to
dopaquinone to form cysteinyldopa,
of which two forms have been
characterized: 5-cystein-S-yl-dopa (5-
cysdopa) and 2-cystein-S-yl-dopa (2-
cysdopa). --CYSDOPAQUINONE --
cyclocysdopaquinolamine --
benzothazlnylalanine--pheomelanin
BIOCHEMISTRY OF MELANIN SYNTHESIS
FUNTION OF MELANIN
Protection of skin by scattering and
absorbing UV LIGHT
Neutraliser of toxic,fre radical oxygen
derivatives,by products of various
inflammatory processes.
Impart different colour to
hair:::black,blond,brunette,red
DISADVANTAGES OF
PIGMENTATION
Pigmentation increases heat
absorption (30%more in black).In
cold climates pale skin has
advantage i.eheat loss by radiation is
reduced
Black people are more liable to
rickets:::::as pigmentation decreases
vit D synthesis