Melanocyte Melanin

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,TRP1,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 membranebound 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  FUSION

OF 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  INSOLUBLE IN ALL SOLVENTS  NITROGENOUS PIGMENT  OXIDATIVE POLYMERISATION OF 5-6DIHROXYINDOLE DERIVED FROM TYROSIN MANUFACTURED IN ELLIPSOIDAL MELANOSOMES

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YELLOWISH TO REDDISH BROWN ALKALI SOLUBLE CONTAIN SULPHUR IN ADDITION TO NITROGEN OXIDATIVE POLYMERISATION OF CYSTINE-S-YI-DOPA VIA 1-4BENZOTHIAZINE INTERMEDIATES MANUFACTURED IN SPHERICAL 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

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STEEL FACTOR -- BINDING TO C-Kit --PHOSPHORYLATE RECEPTOR ---ACTIVATION MITOGEN-ACTIVATED PROTEIN(MAP) ---- Mitf - p (MICROPHTHALMIAASSOCIATED TRANSCRIPTION FACTOR)----------- TRANSCRIPTION OF TYROSINASE,TRP-1,TRP-2

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

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

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UV RAYS BONE MORPHO GENETIC PROTEIN (BMP) RECEPTORS PREVENTS BMP -4 MEDIATED INHIBITION ON MELANONOGENES

MELANIN BIOSYNTHASIS 

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Synthesis of both pigments involves rate limiting step –oxidation of tyrosin to L-DOPA by (RAPER-MANSON STEP)TYROSINASE/TYROSINE OXIDASE/DOPA OXIDASE/MONOPHENOL/DOPAOXYGFEN 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

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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 (5cysdopa) and 2-cystein-S-yl-dopa (2cysdopa). --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