MINIREVIEW
org
The Regulation of Skin
Pigmentation*
Published, JBC Papers in Press, July 16, 2007, DOI 10.1074/jbc.R700026200
Yuji Yamaguchi‡§1, Michaela Brenner‡, and Vincent J. Hearing‡2
From the ‡Laboratory of Cell Biology, NCI, National Institutes of Health,
Bethesda, Maryland 20892 and §Department of Dermatology, Osaka
University Graduate School of Medicine, Osaka 565-0871, Japan
Visible pigmentation of the skin, hair, and eyes depends pri-
marily on the functions of melanocytes, a very minor popula-
tion of cells that specialize in the synthesis and distribution of
the pigmented biopolymer melanin. Melanocytes are derived
from precursor cells (called melanoblasts) during embryologi-
cal development, and melanoblasts destined for the skin origi-
nate from the neural crest. The accurate migration, distribu-
tion, and functioning of melanoblasts/melanocytes determine
the visible phenotype of organisms ranging from simple fungi
to the most complex animal species. In human skin, melano-
cytes are localized at the dermal/epidermal border in a charac-
teristic regularly dispersed pattern. Each melanocyte at the
basal layer of the epidermis is functionally connected to under-
lying fibroblasts in the dermis and to keratinocytes in the over-
lying epidermis. Those three types of cells are highly interactive
and communicate with each other via secreted factors and their
receptors and via cell/cell contacts to regulate the function and
phenotype of the skin.
Overview: Architecture of the Skin
Epidermal melanocytes occur at an approximate ratio of 1:10
among basal keratinocytes and distribute the melanin they pro-
duce to ⬃40 overlying suprabasal keratinocytes via their elon-
gated dendrites and cell/cell contacts (presented schematically
in Fig. 1). Although melanocytes and stem cell keratinocytes in
the basal layer of the epidermis are very stable populations that
proliferate extremely slowly under normal circumstances, ke-
ratinocytes in the upper layers of the epidermis proliferate rel-
atively rapidly. That upward pressure carries them toward the
surface of the skin along with their ingested melanin to form a
critical barrier for the organism against the environment and
the many stresses that originate there. Thus it is not the mela-
nin within melanocytes only, but in combination with the pig-
ment in more superficial layers, that gives skin its characteristic
color. Although melanocytes in other locations of the body (e.g.
hair follicles, eyes, inner ear, etc.) interact with surrounding
cells in manners distinct from those in the epidermis, the basic
processes involved in producing the melanin and the organelles
within which it is synthesized (termed melanosomes) are com-
* This minireview will be reprinted in the 2007 Minireview Compendium,
which will be available in January, 2008. This research was supported by
the Intramural Research Program of the National Institutes of Health, NCI,
Center for Cancer Research, and by a grant-in-aid from the Ministry of
Education, Culture, Sports, and Technology (Japan).
1
Current address: Dept. of Geriatric and Environmental Dermatology,
Nagoya City University, Nagoya 467-8601, Japan.
2
To whom correspondence may be addressed. Tel.: 301-496-1564; Fax: 301-
402-8787; E-mail: hearingv@nih.gov.
SEPTEMBER 21, 2007 • VOLUME 282 • NUMBER 38
This is an Open Access article under the CC BY license.
This paper is available online at www.jbc.
THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 282, NO. 38, pp. 27557–27561, September 21, 2007
Printed in the U.S.A.
parable, as are the factors that regulate melanogenesis. This review
will restrict itself to epidermal pigmentation, and readers inter-
ested in factors influencing pigmentation at other sites should con-
sult recent reviews (1– 6) and books (7, 8) on those topics.
Biochemical Considerations
At this time, more than 125 distinct genes are known that
regulate pigmentation either directly or indirectly (9). Many of
those affect developmental processes critical to melanoblasts,
others regulate the differentiation, survival, etc. of melanocytes,
and yet others regulate distinct processes that affect pigmenta-
tion. Many of those genes (⬎25 at latest count) affect the bio-
genesis or function of melanosomes, the discrete membrane-
bound organelles within which melanins are synthesized.
Melanosomes, which are closely related to lysosomes and are
within the family of lysosome-related organelles (LROs),3
require a number of specific enzymatic and structural proteins
to mature and become competent to produce melanin (10, 11).
As space does not allow a full consideration of melanosome
biogenesis and the specific functions of melanosomal proteins,
readers are referred to several recent reviews on this topic (12,
13). Suffice it to say that the critical enzymes include tyrosinase
(TYR), Tyrp1, and Dct, mutations of which dramatically affect
the quantity and quality of melanins synthesized. Critical struc-
tural proteins include Pmel17 (also known as gp100) and
MART1, both of which are required for the structural matura-
tion of melanosomes. A large number of proteins are involved
in the sorting/trafficking of proteins to melanosomes, and
mutations in any of those typically lead to inherited hypopig-
mentary disorders (8). Melanocytes can produce three distinct
kinds of melanins: two types of eumelanin, which are the pre-
dominant pigments found in dark skin and black hair, and
pheomelanin, which is associated with the red hair/freckled
skin phenotype. As melanosomes mature and their constituent
proteins are delivered, the organelles themselves become car-
gos carried by various molecular motors from the perinuclear
area to the cell periphery (14, 15), after which they are trans-
ferred to neighboring keratinocytes.
The type(s) of melanin produced depends on the function of
melanogenic enzymes and the availability of substrates. Biosyn-
thesis of melanin depends on TYR, and mutations disrupting
TYR function result in an inherited pigmentary disorder known
as albinism. TYR performs the critical rate-limiting activity of
hydroxylating tyrosine to L-3,4-dihydroxyphenylalanine
(DOPA), which is rapidly converted to DOPAquinone. If cys-
teine is available, it will stoichiometrically react with nascent
3
The abbreviations used are: LRO, lysosome-related organelle; ACTH, adre-
nocorticotropic hormone; ASP, Agouti signal protein; DCT, DOPAchrome
tautomerase; DKK, Dickkopf; DHI, 5,6-dihydroxyindole; DHICA, DHI-2-car-
boxylic acid; DOPA, L-3,4-dihydroxyphenylalanine; EMI, epithelial-mesen-
chymal interactions; EMT, epithelial-mesenchymal transitions; bFGF, basic
fibroblast growth factor; HGF, hepatocyte growth factor; HOX, homeobox;
MC1R, melanocortin 1 receptor; MITF, microphthalmia transcription factor;
␣MSH, ␣-melanocyte-stimulating hormone; NGF, nerve growth factor;
POMC, pro-opiomelanocortin; SCF, stem cell factor; TYR, tyrosinase; UV
ultraviolet radiation.
JOURNAL OF BIOLOGICAL CHEMISTRY 27557
MINIREVIEW: The Regulation of Skin Pigmentation
DOPAquinone to yield 3- or 5-cysteinyl DOPAs, which then
oxidize and polymerize, giving rise to yellow-red soluble mela-
nins known collectively as pheomelanins (16, 17). As intramela-
nosomal cysteine is depleted, the excess DOPAquinone spon-
taneously cyclizes to form an orange intermediate known as
DOPAchrome. The carboxylic acid of DOPAchrome will be
spontaneously lost generating 5,6-dihydroxyindole (DHI),
which rapidly oxidizes and polymerizes to form dark brown/
black, high molecular weight insoluble polymers, known as
DHI-melanin. However, if DOPAchrome tautomerase (DCT)
is present, DOPAchrome will tautomerize without losing its car-
boxylic acid group to form DHI-2-carboxylic acid (DHICA), which
can oxidize and polymerize to form yet a third type of melanin,
known as DHICA-melanin, which is a lighter brown color, mod-
erately soluble and of intermediate size (18). Human skin normally
contains mixtures of all three types of melanins, and the ratio of
those in part determines visible pigmentation (19).
Developmental Considerations
Melanoblasts originating in the neural crest must develop,
migrate to appropriate sites, survive, differentiate to melano-
cytes, and then function to produce normal pigmentation pat-
terns. A large number of genes (⬎25) are known to be involved
in those processes, mutations in which cause developmental
pigmentary diseases. In addition to genes expressed by melano-
cytes, signaling factors originating from adjacent tissues play
critical roles in guiding those processes. Epithelial-mesenchy-
mal interactions (EMI) refer to proximate paracrine or juxta-
crine cross-talk between stromal fibroblasts and tissue epithelia
and differ from epithelial-mesenchymal transitions (EMT),
which refer to the transdifferentiation of epithelial cells to a
fibroblast-like phenotype. EMI as well as EMT is required for
the development of various organs; the key signaling pathways
involved in EMI include homeobox (HOX), fibroblast growth
factors, sonic hedgehogs, Wnt/␤-catenin/Lef1, and bone mor-
phogenesis proteins. EMI also play crucial roles in skin devel-
opment and in melanocyte development/function as well. HOX
genes influence the normal development of skin appendages,
the pigmentary system, and stratified epidermis during embry-
ogenesis. Transgenic and knock-out mice studies reveal that
not only HOX genes but also the Wnt/␤-catenin/Lef1 signaling
pathways are involved in melanoblast development. Taken
together, EMI are indispensable for site-specific organogenesis
including liver, lung, kidney, peripheral nerves, digits, skin, and
skin appendages. Readers are referred to recent reviews on this
topic for further information (6 – 8, 20).
Regulation of Constitutive Skin Pigmentation
Skin colors in humans range from extremely fair/light to
extremely dark depending on racial/ethnic background, but the
density of melanocytes in a given area (e.g. the back or arms) is
virtually identical in all types of skin (21). Keratinocytes in fair
skin tend to cluster their poorly pigmented melanosomes above
the nuclei, whereas in dark skin the heavily pigmented melano-
somes are distributed individually in keratinocytes, thus maxi-
mizing their absorption of light (shown schematically in Fig. 1).
There is a large intra-individual variation in melanocyte density
in different areas of the body, e.g. the difference between skin on
27558 JOURNAL OF BIOLOGICAL CHEMISTRY
FIGURE 1. Schematic of human skin architecture from light- and dark-
pigmented skin types. From top to bottom: SC, stratum corneum; G, stratum
granulosum; S, stratum spinosum; B, stratum basale; BM, basement mem-
brane; D, dermis. Cell types: K, keratinocyte; M, melanocyte; F, fibroblast;
shaded oval, melanin granule
the palms/soles compared with other areas of the body. Consti-
tutive melanocyte density in the skin can be affected by the
environment, e.g. by chronic ultraviolet radiation (UV) (which
can increase melanocyte density by 3- or 4-fold) or by toxic
compounds such as hydroquinone (which can selectively and
permanently destroy melanocytes in the skin). Inherited pig-
mentary disorders can also result in increased melanocyte den-
sity (e.g. freckles) or in decreased melanocyte density (e.g. viti-
ligo). (An excellent resource for pigmentary genes, their
functions, and their involvement in pigmentary diseases can be
found at ifpcs.med.umn.edu/micemut.htm.)
Epidermal melanocytes proliferate slowly, if at all, under nor-
mal circumstances, and they are quite resistant to apoptosis
because of their high expression of Bcl2 (22). Melanocyte den-
sity and differentiation is influenced by the environment,
including UV and factors secreted by neighboring keratino-
cytes and fibroblasts (shown schematically in Fig. 2). For exam-
ple, it was recently shown that fibroblasts in the dermis of the
palms/soles secrete high levels of DKK1, which suppresses mel-
anocyte growth and function by inhibiting the Wnt/␤-catenin
signaling pathway (23, 24). DKK1 inhibition of Wnt signaling in
melanocytes dramatically inhibits the melanogenic pathway,
ranging from effects on transcriptional regulators (such as
MITF) to downstream melanogenic proteins. DKK1 also affects
keratinocytes in overlying epidermis, reducing their uptake of
melanin and inducing a thicker less pigmented skin pheno-
type.4 The dermis in adult skin retains the expression patterns
of HOX genes (25), which regulate patterning in primary and
4
Y. Yamaguchi, T. Passeron, H. Watabe, F. Rouzaud, K. Yasumoto, T. Hara, T.
Miki, and V. J. Hearing, submitted for publication.
VOLUME 282 • NUMBER 38 • SEPTEMBER 21, 2007

FIGURE 2. Schematic of receptors, ligands, and other factors that regulate
pigmentation of human skin. Abbreviations for most of these factors,
receptors, proteins, and genes are given in Footnote 3.
secondary axes of the embryo, suggesting that HOX genes reg-
ulate site-specific homeostasis even in adult tissue. This finding
implies that an upstream regulator of DKK1 may be a specific
HOX gene.
One major determinant of pigment phenotype of the skin is
the melanocortin 1 receptor (MC1R), a G protein-coupled
receptor that regulates the quantity and quality of melanins
produced (26, 27). MC1R function is controlled by the agonists
␣-melanocyte-stimulating hormone (␣MSH) and adrenocorti-
cotropic hormone (ACTH) and by an antagonist, Agouti signal-
ing protein (ASP). Activation of the MC1R by an agonist stim-
ulates the expression of the melanogenic cascade and thus the
synthesis of eumelanin, whereas ASP can reverse those effects
and elicit the production of pheomelanin. ␣MSH and ACTH
can also up-regulate expression of the MC1R gene, thus acting
in a positive feedback loop. MC1R function controls the switch
to produce eu- versus pheomelanin, but the mechanism(s)
underlying that switch remains unknown.
In sum, constitutive skin pigmentation is determined by: (a)
the migration of melanoblasts to that tissue during develop-
ment, (b) their survival and differentiation to melanocytes, (c)
the density of melanocytes, (d) the expression/function of enzy-
matic and structural constituents of melanosomes, (e) the syn-
thesis of different types of melanin (eu- and pheomelanin), (f)
the transport of melanosomes to dendrites, (g) the transfer of
melanosomes to keratinocytes, and finally (h) the distribution
of melanin in suprabasal layers of the skin.
Regulation of Facultative Skin Pigmentation
Facultative skin pigmentation is the term coined for
increased skin color due to some type of physiological regula-
tion. Many factors regulate constitutive skin color, the most
SEPTEMBER 21, 2007 • VOLUME 282 • NUMBER 38
MINIREVIEW: The Regulation of Skin Pigmentation
obvious of them being UV in what is commonly termed the
tanning reaction (28, 29). Recent studies have outlined the com-
plex kinetics of responses of the skin to UV radiation, which
result in tanning over the course of several weeks (30).
UV radiation is the most significant factor influencing
human skin pigmentation. As a direct effect of UV, especially
UVA, immediate pigment darkening occurs within minutes
and persists for several hours followed by persistent pigment
darkening, which occurs within several hours and lasts for sev-
eral days (31). These rapid increases in pigmentation do not
result from acute melanin synthesis but rather from the oxida-
tion and polymerization of existing melanin and the redistribu-
tion of existing melanosomes. Delayed tanning also occurs sev-
eral days after UV exposure but takes longer because it involves
the activation of melanocyte function. Exposure to UV leads to
increased expression of MITF (the master transcriptional reg-
ulator of pigmentation) and its downstream melanogenic pro-
teins, including Pmel17, MART-1, TYR, TRP1, and DCT (30,
32), leading eventually to increases in melanin content.
Increased levels of PAR2 in keratinocytes also result from expo-
sure to UV, which increases uptake and distribution of melano-
somes by keratinocytes in the epidermis (33).
Epidermal melanocytes and keratinocytes also respond to
UV exposure by increasing their expression of ␣MSH and
ACTH, which up-regulates the expression and function of
MC1R and consequently enhances melanocyte responses to
those melanocortins. Variants of MC1R that function weakly
are found in individuals with red hair and fair skin who contain
predominantly pheomelanin and have a relative inability to tan.
Endothelin 1 expression by keratinocytes is also increased by
UV and enhances the expression of MC1R, although it works
through its own receptor (EDNRB) on melanocytes. Interleu-
kin-1 secretion by keratinocytes is also elicited by UV and it
stimulates the secretion of ACTH, ␣MSH, endothelin 1, and
bFGF by keratinocytes. Other melanogenic factors produced by
keratinocytes in response to UV include SCF and NGF. The
tanning response also relies on stimulation of secretion of NGF
by keratinocytes, which prevents melanocyte apoptotic cell
death following UV exposure (34). Stimulation of p53 in kerat-
inocytes by UV increases expression of the POMC gene, leading
to increased secretion of ␣MSH and stimulation of MC1R func-
tion in neighboring melanocytes (35). UV can also affect fibro-
blasts in the dermis; growth factors secreted from those cells in
response to UV include HGF, bFGF, and SCF, all factors that
stimulate pigmentation via their receptors on melanocytes (36).
Retinoic acid up-regulates the differentiation (i.e. melanogene-
sis) and proliferation of mammalian melanocytes (37), an effect
that seems to be mediated through increased expression of
melanocortin receptors.
Role of Melanin in Photoprotection of the Skin
Lightly pigmented skin has a dramatically increased risk of
skin cancers, including melanomas, much higher (15–70-fold)
than in darker skin (38, 39). Because skin pigmentation is pri-
marily regulated by the MC1R, its gene is considered a suscep-
tibility gene for melanoma (40).
UV is harmful to human skin because of its production of
various types of cellular damage, most notably oxidative dam-
JOURNAL OF BIOLOGICAL CHEMISTRY 27559
MINIREVIEW: The Regulation of Skin Pigmentation
age and two major types of DNA damage: cyclobutane pyrimi-
dine dimers and 6,4-photoproducts (41). Such molecular
lesions have significant long-term effects on tissue if not
repaired quickly and correctly. There is increasing evidence
that DNA damage/repair itself can induce skin pigmentation.
Small DNA fragments, such as thymine dinucleotides, enhance
pigmentation of melanocytic cells and can stimulate TYR
mRNA levels and responses to MSH (42). p53, which regulates
the cell cycle and the repair of DNA damage, as well as the
induction of apoptosis (32), can also up-regulate POMC/MSH
expression by keratinocytes in response to UV, thereby induc-
ing pigmentation (35).
The involvement of MC1R with UV induction of skin pig-
mentation is complex and is regulated at many levels (43).
MC1R regulates melanocyte function primarily via MITF,
which in turn regulates melanogenesis and dendricity. MITF
expression is stimulated relatively quickly, and significant
increases are seen within 1 day of UV exposure. The down-
stream targets of MITF, e.g. TYR, Pmel17, and DCT, respond
more slowly and reach maxima from 1–3 weeks after UV expo-
sure. It takes several weeks after UV exposure before significant
increases in melanin synthesis or melanocyte density occur. In
addition to its role in pigmentation, MC1R regulates many
other properties of melanocytes, such as the activation of DNA
repair and other anti-photocarcinogenic activities that are
important for protection against the deleterious effects of UV
(44). Although UV increases expression of melanogenic genes
similarly in skin of different racial/ethnic groups (29), there are
some significant differences including melanin redistribution,
protection against DNA damage, and induction of apoptosis in
melanin-containing keratinocytes (21, 45). UV stimulates the
transfer of melanin from the lower epidermis upward and pre-
vents DNA damage in the lower epidermis more significantly in
dark skin than in fair skin (29, 45). UV induces significantly
more apoptosis in dark skin than in fair skin, which suggests a
more efficient removal of UV-damaged cells; this may play a
role in the decreased photocarcinogenesis of darker skin.
Disrupted Regulation of Skin Pigmentation
The regulation of skin pigmentation sometimes goes awry,
leading to pigmentary disorders of many types. Intracellular pH
is an important consideration to the regulation of TYR function
(46), not only because intramelanosomal pH dramatically
affects catalytic functions but also because a correct pH gradi-
ent is critical to the sorting pathway responsible for delivery of
melanosomal proteins (47). There are many instances where
normal levels of functional TYR are produced by melanocytic
cells and yet little or no melanin is formed; it is even thought
that intracellular pH plays an important role in regulating pig-
ment production in various types of skin according to racial/
ethnic origin (48).
TYR function is also regulated by proteasome activity. This
occurs during normal pigmentation and is possibly regulated by
intracellular levels of fatty acids, but it becomes especially
important in the degradation of mutant TYR that occurs in
some forms of albinism. The endoplasmic reticulum-associated
degradation system is exquisitely sensitive to almost any small
perturbation in TYR structure or its chaperone-like protein
27560 JOURNAL OF BIOLOGICAL CHEMISTRY
Tyrp1, leading to extensive hypopigmentation of tissues. Those
interested in the mechanisms of hypopigmentation are referred
to a recent review of the topic (49).
All forms of albinism result from the dysfunction of TYR
and/or other melanogenic proteins, which leads to impaired
pigmentation of the skin, hair and eyes (50). By its nature, only
pigmented tissues are affected; to date, five types of albinism
have been defined that map to five distinct pigment-related
loci. Mutations in any of those genes impact TYR activity either
directly or indirectly: oculocutaneous albinism (OCA) type 1
(TYR) and OCA3 (TYRP1) by leading to proteasomal degrada-
tion of TYR, OCA2 (P) and OCA4 (MATP) by disrupting the
sorting of functional TYR to melanosomes. OA1 (OA1) impairs
melanosome biogenesis and pigmentation by an as yet
unknown mechanism and thereby disrupts the production of
melanin (51).
The biogenesis of melanosomes is closely related to the bio-
genesis of LROs. Mutations that affect LRO formation and/or
function usually also affect pigmentation of melanocyte-con-
taining tissues. The most obvious of these conditions is Her-
mansky-Pudlak syndrome (52), which has pleiotropic clinical
effects (8). So far, eight distinct types of Hermansky-Pudlak
syndrome have been identified, and all map to genes encoding
proteins critical to protein trafficking (53). However, more than
15 such genes have been identified in mice, so ultimately it is
expected that several more forms of Hermansky-Pudlak syn-
drome in humans will be identified. The functional analysis of
those genes is providing tremendous insights into trafficking
mechanisms of proteins in general (54).
Acquired melanin pigmentary disorders can involve a light-
ening or darkening of the skin. Diminished skin color most
commonly results from decreases in epidermal melanin con-
tent, e.g. leukoderma and hypopigmentation are caused by
defects in melanin formation (reviewed in Ref. 8). The absence
or loss of melanocytes is another mechanism of skin lightening,
e.g. as found in vitiligo. In contrast, darkening of the skin may
result from an increased number of melanocytes that produce
excessive amounts of melanin (epidermal melanocytosis, len-
tigines) or increased amounts of melanin produced by a normal
population of melanocytes (epidermal melanosis, freckles).
Alternatively, skin darkening can result from abnormal distri-
bution of melanin (e.g. dermal melanosis, pigmentary inconti-
nence). Up-regulation of the melanogenic paracrine cytokine
network is intrinsically involved in several types of acquired
hypermelanoses (e.g. lentigo senilis and UVB melanosis).
Approaches to Regulating Skin Pigmentation
The regulation of human skin pigmentation has been a long-
standing goal for cosmetic and pharmaceutical applications. It
has implications regarding social standing, cosmetic appear-
ance, and of course photoprotection of the skin against cancer
and photoaging. A number of approaches to stimulate pigmen-
tation have been tried, including activation of MC1R by ago-
nists and bioactive derivatives, topical application of factors
that bypass the MC1R, factors to stimulate TYR function, fac-
5
Y. Yamaguchi, S. G. Coelho, B. Z. Zmudzka, K. Takahashi, J. Z. Beer, V. J. Hear-
ing, and S. A. Miller, submitted for publication.
VOLUME 282 • NUMBER 38 • SEPTEMBER 21, 2007

tors to increase melanosome transfer, etc. Most of those exper-
iments have met with limited or no success, in part because of
the challenge in penetrating the skin barrier and in part because
of the quest for specificity, i.e. to stimulate melanocyte function
without affecting other types of cells in the skin. Interested
readers are referred to a recent review examining approaches to
up-regulating skin pigmentation (55).
Conversely, inhibition of skin pigmentation is also a goal in
many cultures, approaches to which include inhibition of
MC1R function and disruption of TYR activity, for example.
Again, effective agents have had limited success, at least in pro-
viding reversible inhibition of skin pigmentation. Readers inter-
ested in approaches to down-regulating skin pigmentation are
referred to a recent review of that topic (49).
In summary, pigmentation of human skin has dramatic con-
sequences at a variety of distinct levels, such as social attraction
and protection from the environment. The skin is responsive to
many factors that regulate its structure and appearance in an
extremely complex manner.
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