Abstract
Human skin color is predominantly determined by melanin produced in melanosomes within melanocytes and subsequently distributed to keratinocytes. There are many studies that have proposed mechanisms underlying ethnic skin color variations, whereas the processes involved from melanin synthesis in melanocytes to the transfer of melanosomes to keratinocytes are common among humans. Apart from the activities in the melanogenic rate-limiting enzyme, tyrosinase, in melanocytes and the amounts and distribution patterns of melanosomes in keratinocytes, the abilities of the actin-associated factors in charge of melanosome transport within melanocytes also regulate pigmentation. Mutations in genes encoding melanosome transport-related molecules, such as MYO5A, RAB27A and SLAC-2A, have been reported to cause a human pigmentary disease known as Griscelli syndrome, which is associated with diluted skin and hair color. Thus we hypothesized that process might play a role in modulating skin color variations. To address that hypothesis, the correlations of expression of RAB27A and its specific effector, SLAC2-A, to melanogenic ability were evaluated in comparison with tyrosinase, using human melanocytes derived from 19 individuals of varying skin types. Following the finding of the highest correlation in RAB27A expression to the melanogenic ability, darkly-pigmented melanocytes with significantly higher RAB27A expression were found to transfer significantly more melanosomes to keratinocytes than lightly-pigmented melanocytes in co-culture and in human skin substitutes (HSSs) in vivo, resulting in darker skin color in concert with the difference observed in African-descent and Caucasian skins. Additionally, RAB27A knockdown by a lentivirus-derived shRNA in melanocytes concomitantly demonstrated a significantly reduced number of transferred melanosomes to keratinocytes in co-culture and a significantly diminished epidermal melanin content skin color intensity (ΔL* = 4.4) in the HSSs. These data reveal the intrinsically essential role of RAB27A in human ethnic skin color determination and provide new insights for the fundamental understanding of regulatory mechanisms underlying skin pigmentation.
Highlights
Skin color is predominantly determined by the amount and types of melanin produced in melanosomes, melanocyte-specific organelles
The numbers of melanosomes transferred to basal keratinocytes (BKCs) between African-descent and Caucasian skins were compared to understand the ethnic differences in melanosome transfer
People whose ancestors originated from lower latitude areas tend to have darker skin color, whereas people whose ancestors were from higher latitude areas tend to have relatively lighter skin color, indicating that human skin color is one of the characteristics evolutionarily and geographically acquired to protect the skin from harmful ultraviolet radiation [40,41]
Summary
Skin color is predominantly determined by the amount and types of melanin produced in melanosomes, melanocyte-specific organelles. In the process of mammal’s skin color formation, melanin synthesis is launched by the melanogenic enzymes, tyrosinase, dopachrome tautomerase and tyrosinase-related protein-1, mutations in which cause hypopigmented or diluted color of skin [1,2]. The substantial interaction between melanocytes and keratinocytes has been proposed by the anatomical finding that ,36 viable keratinocytes surround each melanocyte to form a specialized cell group called the epidermal melanin unit [7,8]. This ratio of the two cell types is consistently kept despite the extremely wide range of human skin color
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