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Melanocytes and Their Diseases

Yuji Yamaguchi1 and Vincent J. Hearing2

1Medical, AbbVie GK, Mita, Tokyo 108-6302, Japan 2Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 Correspondence: [email protected]

Human are distributed not only in the epidermis and in follicles but also in mucosa, cochlea (ear), iris (eye), and mesencephalon (brain) among other tissues. Melano- cytes, which are derived from the neural crest, are unique in that they produce eu-/pheo- pigments in unique membrane-bound organelles termed , which can be divided into four stages depending on their degree of maturation. Pigmentation production is determined by three distinct elements: enzymes involved in melanin synthesis, proteins required for structure, and proteins required for their trafficking and distribution. Many genes are involved in regulating pigmentation at various levels, and in many of them cause pigmentary disorders, which can be classified into three types: hyperpigmen- tation (including ), (including oculocutaneous [OCA]), and mixed hyper-/hypopigmentation (including dyschromatosis symmetrica hereditaria). We briefly review as a representative of an acquired hypopigmentation disorder.

igments that determine colors somes can be divided into four stages depend- Pinclude melanin, hemoglobin (red), hemo- ing on their degree of maturation. Early mela- siderin (brown), carotene (yellow), and bilin nosomes, especially stage I melanosomes, are (yellow). Among those, play key roles similar to whereas late melanosomes in determining human skin (and hair) pigmen- contain a structured matrix and highly dense tation. Melanin pigments can be classified into melanin deposits. Studies of melanosomes are two major types based on their biosynthetic not only performed in medicine but also in ar- pathways, as updated and reviewed elsewhere: chaeology because various morphologies of www.perspectivesinmedicine.org eumelanin (dark brown and black) and pheo- melanosomes remaining in fossils serve as clues melanin (yellow, red, and light brown) (Simon to hypothesize the colors of dinosaurs (Li et al. et al. 2009; Hearing 2011; Kondo and Hearing 2012). 2011). Eu-/pheo-melanin pigments are pro- Melanocytes can be defined as cells that pos- duced and deposited in melanosomes, which sess the unique capacity to synthesize melanins belong to the LRO (-related organelle) within melanosomes. Factors related to mela- family in that they contain acid-dependent hy- nin production within melanocytes can be di- drolases and lysosomal-associated membrane vided into three groups as previously reviewed: proteins (Raposo and Marks 2007). Melano- structural proteins of melanosomes, enzymes

Editors: Anthony E. Oro and Fiona M. Watt Additional Perspectives on The Skin and Its Diseases available at www.perspectivesinmedicine.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a017046 Cite this article as Cold Spring Harb Perspect Med 2014;4:a017046

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Y. Yamaguchi and V.J. Hearing

required for melanin synthesis, and proteins re- Heregulin or Neu differentiation factor) regu- quired for melanosome transport and distribu- lates the survival and proliferation of Schwann tion (Yamaguchi and Hearing 2009). We briefly cell precursors and determines the fate of update the recent findings regarding pigmenta- Schwann cells and melanocytes depending on tion-related factors. high and low expression levels, respectively, Disruptions of the functions of many pig- and that secreted signals, including IGF (insu- mentation-related factors are known to cause lin-like growth factor) and PDGF (platelet-de- pigmentary disorders and a curated list of those rived growth factor) enhance devel- aresummarizedandupdated at the homepage of opment (Adameyko et al. 2009). Those findings the European Society for Pigment Cell Research may explain the facts that patients with neurofi- (www.espcr.org/micemut). Those disorders in- bromatosis type 1, who develop neurofibromas clude , hypopigmentation, consisting mainly of Schwann cells, are hyper- and mixed hyper-/hypopigmentation disor- pigmented, and that segmental vitiligo mostly ders, which are subdivided into congenital or occurs along with the affected innervation zones acquired status (Table 1). Their diagnosis de- or dermatomes. pends on the size, location (involved site(s) of Taken together, melanocytes in the skin the body), and morphology (isolated, multiple, eventually derive from the neural crest and ei- map-like, reticular, or linear) of the lesions. Hy- ther differentiate directly from neural crest cells popigmentation disorders are subclassified into via a dorsolateral path or derive from Schwann those associated with complete or incomplete cell precursors via a ventral path after detaching . from the nerve. Various transcription factors, including Hmx1 and Krox20, act as intrinsic factors that regulate the fate of these cell types, MELANOCYTE DEVELOPMENT which are modulated by extrinsic factors in- As recently summarized (Kawakami and Fisher cluding Neuregulin-1, IGF, and PDGF. 2011; Sommer 2011), melanocytes in the skin are exclusively derived from the neural crest. MELANOCYTE HETEROGENEITY Melanocytes used to be thought to derive di- rectly from neural crest cells migrating via a Human melanocytes reside not only in the epi- dorsolateral path (between the ectoderm and dermis and in hair follicles but also in mucosa, dermamyotome of somites) during embryo- cochlea of the ear, iris of the eye, and mesen- genesis, whereas neurons and glial cells were cephalon of the brain as well as other tissues thought to derive from neural crest cells migrat- (Plonka et al. 2009). As far as mouse melano- www.perspectivesinmedicine.org ing via a ventral path between the neural tube cytes are concerned, Aoki et al. reported that and somites. Adameyko et al. (2009) recently noncutaneous (ear, eye, and harderian gland) challenged this idea and reported that melano- and dermal melanocytes are different from epi- cytes migrate and differentiate from nerve-de- dermal melanocytes in that the former do not rived Schwann cell precursors, whose fate is de- respond to KIT stimulation but respond well to termined by the loss of Hmx1 homeobox gene ET3 (endothelin 3) or HGF (hepatocyte growth function in the ventral path. Schwann cell pre- factor) signals (Aoki et al. 2009), suggesting the cursors detaching from the nerve differentiate heterogeneity of mouse melanocytes. They also into melanocytes, whereas precursors that stay reported that noncutaneous or dermal melano- in contact with nerves eventually differentiate cytes cannot participate in regenerating follicu- into Schwann cells. Those authors also showed lar melanocytes using the hair reconstitution that Schwann cells remain competent to form assay, unlike epidermal melanocytes (Aoki et melanocytes using Krox20 (early growth re- al. 2011). Studies by Tobin’s group also support sponse 2 or Egr2)-Cre loci crossed to YFP re- the hypothesis that follicular and epidermal me- porter strains. They also showed that Neureg- lanocytes in human skin are different regarding ulin-1 (also known as glial growth factor, their responses to various biological response

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Melanocytes and Their Diseases

Table 1. Pigmentary disorders and possible responsive genes Representative disease Disease brief description Locus Mechanism(s) of action Hyperpigmentation disorder Congenital Generalized Widespread lentigines without associated noncutaneous 4q21.1-q22.3 abnormalities LEOPARD Multiple lentigines, congenital PTPN11 Protein phosphatase, syndrome cardiac abnormalities, ocular nonreceptor type 11 hypertelorism, and retardation of growth A multiple neoplasia syndrome PRKAR1A Protein kinase A regulatory characterized by spotty skin subunit 1a pigmentation, cardiac and other myxomas, endocrine tumors, and psammomatous melanotic schwannomas Peutz–Jeghers Pigments on lips and STK11/LKB1 Serine/threonine kinase 11 syndrome palmoplantar area Others cell nevus, , , , nevus Ohta, dermal , nevus Ito, Mongolian spot, ephelides, acropigmentio reticularis, Spitzenpigment/acropigmentation, inherited patterned lentiginosis, Laugier–Hunziker–Baran syndrome, Cronkhite–Canada syndrome Acquired Melasma/chloasma Symmetric malar brownish WIF-1 and Wnt inhibitory factor-1/Wnt and hyperpigmentation others lipid-metabolism-related genes Others Senile lentigines/, Riehl’s melanosis, labial melanotic macule, penile/vulvovaginal melanosis, erythromelanosis follicularis faciei (Kitamura), pigmentation petaloides actinica tanning, postinflammatory pigmentation, chemical/drug-induced pigmentation, pigmentary demarcation lines, foreign material deposition Hyperpigmentation related with systemic disorders and others Mastocytosis Darier’s sign KIT and others Urticaria pigmentosa www.perspectivesinmedicine.org Neurofibromatosis Neurofibromas and cafe´-au-lait NF1 RAS GTPase-activating protein; type 1 spots/von Recklinghausen’s Neurofibromin 1 disease Sotos syndrome Tall stature, advanced bone age, NSD1 Nuclear receptor binding SET typical facial abnormalities, domain protein 1 and developmental delay POEMS syndrome Polyneuropathy, organomegaly, VEGF and Vascular endothelial growth factor endocrinopathy, M-protein, others and angiogenetic factors and skin changes Cantu syndrome Hypertrichosis, macrosomia, ABCC9 ATP-binding cassette, subfamily C, osteochondrodysplasia, and member 9 cardiomegaly McCune–Albright Clinical triad of fibrous dysplasia GNAS Guanine nucleotide-binding syndrome of bone, cafe-au-lait skin spots, protein, a stimulation/ and precocious puberty stimulatory G protein Bloom syndrome Photosensitivity and increased BLM RecQ helicase family risk of malignancy Continued

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Y. Yamaguchi and V.J. Hearing

Table 1. Continued Representative disease Disease brief description Locus Mechanism(s) of action Others Naegeli syndrome, Watson syndrome, metabolism/enzyme disorders, endocrine disorders, nutritional disorders, collagen diseases, liver dysfunction, kidney dysfunction, infectious diseases Hypopigmentation disorder Congenital Oculocutaneous Hypopigmentation, TYR GPR143 Melanosomal enzyme G-protein- albinism type 1 coupled receptor (GPR143); melanosome biogenesis signal transduction Oculocutaneous OCA2 Melanosome biogenesis and size albinism type 2 Oculocutaneous TYRP1 Melanosomal enzyme; stabilizing albinism type 3 factor Oculocutaneous SLC45A2 Solute transporter; previously albinism type 4 named as membrane-associated transporter protein (MATP) Hermansky–Pudlak Hypopigmentation, bleeding HPS1 Membrane protein; organelle syndrome type 1 caused by thrombopenia biogenesis and size Hermansky–Pudlak AP3B1 b3 Subunit of adaptor protein 3 syndrome type 2 complex; organellar protein routing Hermansky–Pudlak HPS3 Organelle biogenesis syndrome type 3 Hermansky–Pudlak HPS4 Organelle biogenesis and size syndrome type 4 Hermansky–Pudlak HPS5 Biogenesis of lysosome-related syndrome type 5 organelles complex-2 Hermansky–Pudlak HPS6 Biogenesis of lysosome-related syndrome type 6 organelles complex-2 Hermansky–Pudlak DTNBP1 , component of the syndrome type 7 biogenesis of lysosome-related organelles complex-1 (BLOC1) www.perspectivesinmedicine.org Hermansky–Pudlak BLOC1S3 Component of the BLOC1 protein syndrome type 8 transport complex Hermansky–Pudlak PLDN Vesicle-docking and fusion syndrome type 9 Chediak–Higashi Hypopigmentation, infection LYST Organelle biogenesis and size; syndrome caused by immunodeficiency membrane protein Hypopigmentation, MYO5A Melanosome transport; type 1 hepatosplenomegaly, type Va/dilute mice pancytopenia, immunologic disorder, and central nervous system abnormalities Griscelli syndrome RAB27A Melanosome transport; RAS- type 2 associated protein/ashen mice Griscelli syndrome MLPH Melanosome transport; type 3 /leaden mice hydroxylase PAH Phenylalanine hydroxylase deficiency Continued

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Melanocytes and Their Diseases

Table 1. Continued Representative disease Disease brief description Locus Mechanism(s) of action White spotting, megacolon, and KIT Receptor for SCF; required for other neural crest defects melanoblast survival and homing Waardenburg White spotting and small or PAX3 ; neural tube syndrome type 1 absent eyes development and 3 Waardenburg White spotting, head blaze, pale MITF SNAI2 Transcription factor; master syndrome type 2 hair and skin, neural crest, regulator of melanocyte lineage and other organ defects transcription factor Waardenburg–Shah White spotting, megacolon, and EDN3 SOX10 Melanoblast/neuroblast growth syndrome other neural crest defects and differentiation factor; transcription factor Hypomelanosis of Hypopigmentation along Duplication of Ito Blaschko lines/neural Xp11.3- disorders p11.4 and random X inactivation Hirschsprung’s White spotting, megacolon, and EDNRB Endothelin receptor B disease type 2 other neural crest defects Fraser syndrome Microphthalmia/anophthalmia, FREM2 Extracellular protein related with patches of discolored or white epithelial–mesenchymal fur interactions Charcot–Marie– Pale skin, alopecia, clumped FIG4 Phosphatidylinositol-(3,5)- Tooth disease melanosomes, and immune bisphosphatase 5-phosphatase; type 4J effects late endosome-lysosome axis Menkes disease Copper transport disorders, ATP7A ATPase, copper-transporting a kinky hair polypeptide Wilson disease Copper transport disorders, ATP7B ATPase, copper-transporting b kinky hair polypeptide Multiple organ dysfuctions CTNS Cystinosin, cysteine/Hþ caused by cystine crystal symporter, which exports accumulation cysteine out of lysosomes

www.perspectivesinmedicine.org Others Cross–McKusick–Breen syndrome, Acquired Vitiligo Lesions depigmented completely NALP1 MHCI NLR family, pyrin domain at initiation phase and MHCII containing 1/major- pigmented orifices of hair PTPN22 LPP histocompatibility-complex follicles at recovering phase IL2RA class I molecules and class II and hyperpigmented ridges UBASH3A molecules/protein tyrosine surrounded by the lesion at C1QTNF6 phosphatase, nonreceptor type stable/intractable phase RERE 22/LIM domain containing GZMB preferred translocation partner FOXP1 in lipoma/ubiquitin associated CCR6 and SH3 domain containing A/ and others C1q and tumor-necrosis-factor- related protein 6 gene/- dipeptide repeats/ granzyme B Continued

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Y. Yamaguchi and V.J. Hearing

Table 1. Continued Representative disease Disease brief description Locus Mechanism(s) of action Vogt–Koyanagi– Bilateral, chronic, diffuse HLA-D IL17 HLA-D gene locus including HLA- Harada disease granulomatous uveitis with and others DRB1, DR1, DR4, DQA1, and poliosis, vitiligo, central DQB1/interleukin-17 nervous system, and auditory signs Others Sutton nevus/phenomenon, malignancy-induced hypopigmentation, postinflammatory hypopigmentation, , senile leukodermachemical/drug-induced leukoderma Hypopigmentation related with systemic disorders and others Ataxia telangiectasia Cancer predisposition and ATM Ataxia-telangiectasia mutated, neurodegenerative disorders DNA-damage response, signal transduction, and cell-cycle control Congenital profound deafness MITF Transcription factor; master and generalized regulator of melanocyte lineage hypopigmentation Tuberous sclerosis Seizures, mental retardation, and mTOR Tuberin and hamartin cutaneous angiofibromas/ development of multiple hamartomas/ash leaf macule Werner synderome Adult onset segmental progeroid WRN Werner syndrome, RecQ helicase- syndrome like Others Alezzandrini syndrome, Preus syndrome, Tothmund–Thomson syndrome, infectious diseases Mixed hyper-/hypopigmentation disorder Congenital Incontinentia Four stages: vesicles, verrucous NEMO/ Nuclear factor-kB essential pigmenti lesions, hyperpigmentation, IKBKG modulator/inhibitor of k light and hypopigmentation polypeptide gene enhancer in B cells, kinase g Dyschromatosis Mixture of hyperpigmented and ADAR1 Double-stranded RNA-specific www.perspectivesinmedicine.org symmetrica hypopigmented macules adenosine deaminase hereditaria distributed on the face and the dorsal aspects of the extremities Xeroderma UV-induced carcinogenesis XPA Xeroderma pigmentosum type A pigmentosum type A Xeroderma ERCC3 Excision repair cross- pigmentosum complementation group 3; type B nucleotide excision repair (NER) Xeroderma XPC Xeroderma pigmentosum type C pigmentosum type C Xeroderma ERCC2 Excision repair cross- pigmentosum complementation group 2; type D nucleotide excision repair (NER) Continued

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Melanocytes and Their Diseases

Table 1. Continued Representative disease Disease brief description Locus Mechanism(s) of action Xeroderma DDB2 Double-stranded DNA-binding pigmentosum protein 2 type E Xeroderma ERCC4 Excision repair cross- pigmentosum complementation group 4; type F nucleotide excision repair (NER) Xeroderma ERCC5 Excision repair cross- pigmentosum complementation group 5; type G nucleotide excision repair (NER) Xeroderma POLH Polymerase (DNA directed), h pigmentosum (RAD 30 related) type V Acquired Photoleuko- melanoderma, drug-induced disorders

modifiers, including aMSH (Tobin 2011). Ad- et al. 2012). Although the relevance to melano- ditionally, Li et al. (2010) also reported that cytes has not been elucidated, a series of studies dermal melanocyte stem cells derived from gla- from Chang’s group showed that the expression brous human foreskin (i.e., with no hair folli- patterns of homeotic genes (HOX genes, which cles) can differentiate into functional epidermal are expressed in a nested pattern along devel- melanocytes using a three-dimensional skin opmental axes) determine positional identities equivalent model. within the human body (Chang 2009) and that These results make us wonder whether hu- a long noncoding RNA, which used to be con- man fetal and/or adult melanocytes are hetero- sidered to have nonspecific roles, has site-spe- geneous. Human adult melanocytes in skin on cificity (Rinn et al. 2007) and maintains active the palms and soles may be different from me- chromatin to coordinate HOX gene expression lanocytes derived from other sites of the skin (Wang et al. 2011). Additionally, the expression www.perspectivesinmedicine.org based on the facts that melanocyte migration levels of distal-specific HOXA13 are up-regu- stops at the palms and soles during embryogen- lated in adult fibroblasts in the skin of paws esis and that skin on the palms and soles is of mice, thereby inducing the expression of hypopigmented and contains a fivefold lower Wnt5A, a morphogen required for distal devel- density of melanocytes than at other skin areas. opment, in fibroblasts and of keratin 9, a distal Additionally, fibroblasts in the dermis of the specific marker of epidermis, in keratinocytes palms and soles secrete high levels of DKK1 (Rinn et al. 2008). These results obtained in (dickkopf1), which is an inhibitor of the Wnt studies of mice support the hypothesis that signaling pathway and suppresses the prolifera- mesenchymal-epithelial interactions play im- tion and differentiation of those melanocytes portant roles in maintaining the site-specificity (Yamaguchiet al. 2004). Preliminary results ob- of the skin (Yamaguchi et al. 2005). tained from human fetal melanocytes cultured Taken together, human fetal and adult me- from four different body sites (scalp, back, ab- lanocytes may be heterogeneous/site-specific domen, and sole) indicate that palmoplantar because those melanocytes are also regulated melanocytes express high levels of DKK1, and maintained by site-specific HOX genes, TBX4, WIF1, FGF7, and CHI3L1 (Nakamura whose expression patterns are eventually deter-

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mined by chromatins and long noncoding celerate ectopic pigmentation or differentiation RNAs. That melanocyte heterogeneity may be within the niche, thereby causing the physiolog- affected both by intrinsic factors, including a ical aging of MelSCs (Nishimura et al. 2005). site-specific transcription factor, HOX, and by Genotoxic stress also results in the depletion extrinsic factors secreted by surrounding resi- of MelSCs and in the irreversible hair graying dent cell types: fibroblasts and keratinocytes. caused by their unscheduled differentiation (In- The fact that acral is different from omata et al. 2009). Other factors involved in hair other types of melanoma (Curtin et al. 2005), graying include defective TGF-b signaling from especially in that AMP kinase-related NUAK2 hair follicle stem cells and abnormal regulation expression levels are high in patients with poor of the Notch and Wnt signaling pathways (Ni- prognosis acral melanoma (Namiki et al. 2011), shimura 2011). Similar mechanisms may be in- may also support the idea that melanocytes are volved in the pathogenesis of senile leukoderma, heterogeneous. although this disease concept is not yet well ac- cepted worldwide. Ectopic up-regulation of MelSC function MELANOCYTE STEM CELLS caused by aging and/or UV-irradiation may be As recently summarized by Nishimura (2011), involved in the formation of senile lentigines/ research on melanocyte stem cells (MelSCs) is lentigo and other age-related hyperpigmenta- also in the spotlight. A series of studies by her tion disorders. Cosmetic companies usually fo- group showed that MelSCs are immature mela- cus on developing antiaging products, but the noblasts expressing high levels of dopachrome senescence process is beneficial in preventing tautomerase (DCT) and low levels of Kit located tumorigenesis. Generally speaking, senescent in the lower permanent portion of the hair fol- cells are defined as cells with permanent pro- licle (Nishimura et al. 2002). MelSCs direct- liferative arrest irrespective of physiological mi- ly adhere to hair follicle stem cells whose high togenic stimuli, expressing b-galactosidase and expression levels of collagen XVII (COL17A1, senescence-associated heterochromatic foci. BP180, or BPAG2) play important roles in Factors that initiate and maintain the senescence maintaining MelSCs, which do not express program include BRAF, NRAS, p16INK4a, COL17A1 (Tanimura et al. 2011). MelSCs surely p21Waf1, p53, and pRb (Haferkamp and Rizos serve as a melanocyte reservoir for the pigmen- 2010). Benign nevi typically remain growth ar- tation of both the hair and the skin based on the rested and contain abundant numbers of senes- fact that repigmentation usually occurs at the cent cells, although senescent cells are absent in orifices of hair follicles in the skin of vitiligo advanced and in normal melano- www.perspectivesinmedicine.org patients. Future studies may elucidate the mech- cytes. The expression of BRAFV600E in mela- anism(s) by which MelSCs are maintained and nocytes increases the synthesis and secretion of regulated in skin at the palms and soles, where IGFBP7, which may be required for melanocyte hair follicles do not physiologically exist. senescence, based on multidisciplinary studies, including the use of shRNA specific for IGFBP7 (Wajapeyee et al. 2010). MELANOCYTE SENESCENCE Future studies regarding melanocyte senes- The aging process in human skin eventually re- cence will contribute to both tissue regeneration sults not only in brittle/thin/inelastic skin and (hair graying and antiaging) and melanoma senile lentigines/lentigo but also hair graying treatment. and senile leukoderma. As for hair graying, Nishimura et al. (2005) reported that a Bcl2 FACTORS THAT REGULATE MELANIN deficiency accelerates the selective apoptosis of PRODUCTION WITHIN MELANOCYTES MelSCs, thereby disturbing the self-mainte- nance of MelSCs, resulting in hair graying. Pigment-specific factors that modulate mela- They also reported that mutations in MITF ac- nin production within melanocytes are usually

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Melanocytes and Their Diseases

Melanosome trafficking proteins Slp2-a

RILP ciliobrevins Melanosomal structural proteins Myosin Va melanophilin F- Rab27a IV IV GPNMB/DC-HIL/ osteoactivin Enzymes involved in IV melanin synthesis III TYRP1 TYR TRP2/DCT MART-1 III

II MATP/ OA1 P SLC45A2 Dynein Pmel17/Silv/ II GP100 ( ) BLOC-1

I I AP-1 TGN

Key transcription factors Golgi PAX3 ER SOX9 SOX10 MITF LEF-1/TCF DICER CREB BIM cAMP

MC1R

Figure 1. Factors that regulate melanin production within melanocytes. Critical factors consist of proteins that affect melanosome structure (Pmel17, MART-1, and GPNMB), proteins that modulate melanin synthesis either

www.perspectivesinmedicine.org directly or indirectly (TYR, TYRP1, DCT,BLOC-1, OA1, P,and SLC45A2), proteins involved in the trafficking of melanosome proteins or the intracellular transport of melanosomes (microtubules, F-actin, kinesin, dynein, Rab27a, melanophilin, myosin Va,RILP,ciliobrevins, and Slp2-a), and melanocyte-specific transcription factors (PAX3, SOX9/10, LEF-1, CREB, DICER, and MITF). Melanosomes mature through distinct stages, noted as I, II, III, and IV in this diagram.

located within, on, or close to melanosomes and sion and function of many of those pigment- can be divided into three types (Fig. 1): proteins specific factors. We briefly update several im- involved in melanosome structure, proteins that portant findings since our review published sev- regulate melanin synthesis, and proteins in- eral years ago (Yamaguchi and Hearing 2009). volved in the intracellular trafficking of melano- some components and the transport of mela- Melanosomal Structural Proteins nosomes to the cell’s periphery (Yamaguchiand Hearing 2009). Transcription factors specifi- Three important structural proteins that form cally expressed by melanocytes and by melano- melanosomes include PMEL17/Silv/GP100, ma cells (especially MITF) regulate the expres- MART-1 (melanoma antigen recognized by

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T cell-1), and GPNMB (glycoprotein non-met- pH may play important roles for regulating the astatic melanoma protein b)/DC-HIL/osteo- appropriate enzymatic functions in melanin activin. PMEL17 forms an amyloidogenic fibril synthesis as well as the processing and function depending on the critical acidic pH (5.0 + 0.5) of melanosomal structural proteins. within melanosomes (Pfefferkorn et al. 2010). Studying PMEL17 mutations can be useful Melanosome Trafficking Proteins to investigate the conversion between physio- logical/benign and pathological amyloid pro- Melanin granules are transported from the peri- teins (Watt et al. 2011). MART-1, which is nuclear area to the periphery of melanocytes abundant in early melanosomes, is required and are eventually transferred to adjacent kera- for the maturation of PMEL17 (Hoashi et al. tinocytes (Yamaguchi and Hearing 2009). Early 2005). GPNMB, which is highly homologous melanosomes, produced via the trans-Golgi to Pmel17 but lacks the RPT domain (imperfect network and/or endocytosis, originate in the repeats of , serine, and threonine-rich perinuclear area and then mature to late (pig- motifs), is a melanosome-specific and proteo- mented) melanosomes as they move toward the lytically released protein, which is abundant in periphery of the melanocyte (i.e., the den- late melanosomes (Hoashi et al. 2010). GPNMB drites). In this trafficking pathway, kinesin (pro- is critical for the formation of melanosomes in a grade) and dynein (retrograde) act like wheels MITF-independent fashion (Zhang et al. 2012). for melanosomal cargo and microtubules func- These structural melanosomal proteins provide tion like rails. The clathrin adaptor AP-1 is re- scaffold materials to the enzymes required for ported to interact with the kinesin motor melanin deposition and on which the melanins KIF13A, suggesting the role of adaptor proteins are deposited. in melanosome trafficking (Delevoye et al. 2009). The melanosomal cargo is transferred from microtubules to F-actin, which acts as a Enzymes Involved in Melanin Synthesis rail, at the periphery of the melanocyte. Semi- There are three key enzymes that play critical automated analysis of organelle movement and roles in melanin synthesis within melanosomes: membrane content reveals the involvement of TYR (), TYRP1 (tyrosinase related Rab27a and its complex in the regulation of protein-1), and TRP2/DCT (dopachrome tau- this transfer (Hume et al. 2011). Rab27a, mela- tomerase). Many factors, including BLOC-1, nophilin, and myosin Vaare connected to mela- OA1, P, and SLC45A2 (previously known as nosomes in that order and function like wheels. MATP) influence the trafficking and thus the Finally, Slp2-a may regulate melanosomal cargo www.perspectivesinmedicine.org function of these enzymes. Of note, metal ions exocytosis. Recent findings show that melanor- including zinc and copper serve as catalysts egulin regulates retrograde melanosome trans- and/or chelators when melanin is synthesized port via the interaction with RILP (-inter- (Simon et al. 2009) and metal remnants in fos- acting lysosomal protein) and its complex sils enable us to predict the colors of dinosaurs (dynactin subunit 1) (Ohbayashi et al. 2012). (Wogelius et al. 2011), in addition to determin- Ciliobrevins were discovered as small-molecule ing the configurations of melanosomes (Li et inhibitors of the AAAþ (ATPases associated with al. 2012). Cystinosin, a cysteine/Hþ symporter diverse cellular activities) ATPase dynein (Fire- that exports cysteine out of lysosomes, is the stone et al. 2012). Studies further elucidating gene associated with cystinosis, a rare autosomal melanosome trafficking might be enhanced in recessive disorder with multiple organ dysfunc- the near future characterizing these factors. tions including hypopigmentation (Chiaverini et al. 2012). Additionally, NAD(P)H:quinone Melanocyte-Specific Transcription Factors oxidoreductase-1 enhances melanogenesis by increasing the levels of TYR protein (Choi et MITF has been investigated intensively among al. 2010). The regulation of intramelanosomal the many transcription factors known to reg-

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Melanocytes and Their Diseases

ulate melanocyte function. MITF itself is reg- Congenital Hyperpigmentation Disorders ulated by many other transcription factors, including PAX3 (a neural-crest-associated tran- Congenital hyperpigmentation disorders in- scription factor), SOX9, SOX10, LEF-1/TCF (a clude those involving epidermal hyperpigmen- downstream regulator of Wnt signaling path- tation (nevus cell nevus, Spitz nevus, and nevus way), and CREB (cAMP responsive-element- spilus), dermal hyperpigmentation (blue ne- binding protein, which is phosphorylated by vus, nevus Ohta, dermal melanosis, nevus Ito, signals via MC1R, melanocortin-1 receptor) and Mongolian spot), ephelides, acropigmen- (Yamaguchi and Hearing 2009). tatio reticularis, Spitzenpigment/acropigmen- Fisher’s group recently reported that MITF tation, and lentiginosis (generalized lentigino- directly up-regulates DICER, an endoribo- sis, LEOPARD syndrome, inherited patterned nuclease in the RNase III family that cleaves lentiginosis, Carney complex, Peutz–Jeghers double-stranded RNA and pre-microRNA into syndrome, Laugier–Hunziker–Baran syndrome, short RNA fragments (20–25 nucleotides long), and Cronkhite–Canada syndrome). on melanocyte differentiation (Levy et al. 2010). The responsible locus for generalized lenti- Enhanced DICER expression plays a crucial role ginosis, characterized by widespread lentigines in melanocyte survival via the posttranscrip- without systemic involvement, has been local- tional processing of the pre-microRNA-17  ized to chromosome 4q21.1-q22.3 (Xing et al. 92 cluster, which leads to the down-regulation 2005). LEOPARD syndrome is characterized of BIM, a proapoptotic factor. by multiple lentigines, congenital cardiac ab- normalities, ocular hypertelorism, and retarda- tion of growth, and many reports have shown PIGMENTARY DISORDERS its association with mutations in the PTPN11 Assummarized above,the regulation of pigmen- (protein tyrosine phosphatase, nonreceptor tation involves many factors required for devel- type 11) gene located at chromosome 12q24 opment, heterogeneity, regeneration, and senes- since Legius et al. (2002) first reported the cence of melanocytes and their precursors, as association with Noonan syndrome. Carney well as those involved in determining melano- complex, a multiple neoplasia syndrome char- some structure, melanin synthesis, the traffick- acterized by spotty skin pigmentation, cardiac ing of melanosomal components and the trans- and other myxomas, endocrine tumors, and port and distribution of melanosomes, and psammomatous melanotic schwannomas, has melanocyte-specific transcription factors that been shown to be caused by mutations in control the expression and function of all those PRKAR1A (protein kinase A regulatory subunit www.perspectivesinmedicine.org genes. More than 350 loci are currently known to 1a), a tumor-suppressor gene (Kirschner et al. be directly or indirectly involved with those pro- 2000). Peutz-Jeghers syndrome, which predis- cesses in mice and mutations of many of those poses to benign and malignant tumors of many genes have been associated with human pigmen- organ systems, has been reported to be asso- tary disorders. Those include hyperpigmen- ciated with mutations in STK11 (serine/threo- tation, hypopigmentation, and mixed hyper-/ nine protein kinase)/LKB1 (Hemminki et al. hypopigmentation disorders and can be diag- 1998). nosed by size (systemic or localized), comorbid- ities, site of the involvement, and patterns/ Acquired Hyperpigmentation Disorders shapes of the lesions (Table 1). Those are sub- classified into congenital and acquired disorders Acquired hyperpigmentation disorders include and in addition hypopigmentation disorders senile lentigines/lentigo, melasma/chloasma, can also be subclassified into complete and in- Riehl’s melanosis, labial melanotic macule, pe- complete depigmentation. Among the many nile/vulvovaginal melanosis, erythromelanosis pigmentary disorders summarized in Table 1, follicularis faciei Kitamura, UV-induced pig- we focus on vitiligo because of space limitations. mentation (tanning and pigmentation petal-

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Y. Yamaguchi and V.J. Hearing

oides actinica), postinflammatory pigmenta- drome, characterized by childhood overgrowth tion (friction melanosis and ashy dermatosis), with advanced bone age, craniofacial dysmor- chemical/drug-induced pigmentation (poly- phic features including macrocephaly and chlorinated biphenyl, arsenic, 5-FU, bleomycin, learning difficulties, results from the haploin- cyclophosphamide, methotrexate, chlorproma- sufficiency of NSD1 (nuclear receptor binding zine, phenytoin, tetracycline, and chloroquine), SET domain protein 1) (Kurotaki et al. 2002). pigmentary demarcation lines, foreign material POEMS syndrome (polyneuropathy, organo- deposition (such as carotene, silver, gold, mer- megaly, endocrinopathy, M-protein, and skin cury, bismuth, and ). Hyperpigmenta- changes) is a multisystem disorder associated tion related with systemic disorders includes with plasma cell dyscrasia, and patients with metabolism/enzyme disorders (hemochroma- POEMS syndrome show up-regulated serum tosis, Wilson’s disease, Gaucher’s disease, Nie- levels of angiogenetic factors including VEGF mann–Pick’s disease, amyloidosis, , (vascular endothelial growth factor) and HGF , and porphyria cutanea (hepatocyte growth factor) (Yamada et al. tarda), endocrine disorders (Addison’s disease, 2013). Cantu syndrome, characterized by hy- Cushing syndrome, and hyperthyroidism), nu- pertrichosis, macrosomia, osteochondrodys- tritional disorders (pellagra, vitamin B12 defi- plasia, and cardiomegaly, is reported to be ciency, folic acid deficiency, vagabond’s disease, caused by mutations in ABCC9 (ATP-binding and prurigo pigmentosa), mastocytosis, colla- cassette, subfamily C, member 9) (van Bon et al. gen diseases, liver dysfunction, and kidney dys- 2012). McCune–Albright syndrome results from function. Hyperpigmentation can also be relat- somatic mutations of the GNAS gene (G-pro- ed with infectious diseases (measles, syphilis, tein a-subunit) especially mutations in Gsa and Malassezia furfur) and syndromes (von (stimulatory G protein) (Dumitrescu and Col- Recklinghausen’s disease, Sotos syndrome, lins 2008). The causative gene for Bloom syn- POEMS syndrome, Naegeli syndrome, Cantu drome, with photosensitivity and increased risk syndrome, McCune–Albright syndrome, Wat- of malignancy, is BLM (Bloom syndrome, RecQ son syndrome, and Bloom syndrome). helicase-like), localized at chromosome 15q26.1 Bioinformatics studies have shown that (German et al. 1994). genes responsible for melasma include Wnt and lipid metabolism-related genes in addition Congenital Hypopigmentation Disorders to melanogenic markers (Kang et al. 2011) and that reduced expression levels of WIF-1 (Wnt Congenital hypopigmentation disorders in- inhibitory factor-1) in keratinocytes and/or clude various types of oculocutaneous albin- www.perspectivesinmedicine.org fibroblasts may play roles in the development ism (OCA1–4, Hermansky–Pudlak syndrome, of melasma (Kim et al. 2013). Patients with Chediak–Higashi syndrome, and Griscelli syn- mastocytosis usually carry the D816 V KITmu- drome), Cross–McKusick–Breen syndrome, tation and a bioinformatics study shows that phenylketonuria, piebaldism, Waardenburg syn- those patients show the up-regulation of genes drome, nevus depigmentosus, hypomelanosis involved in innate and inflammatory immune of Ito, Hirschprung’s disease, Charcot–Marie– responses, including interferon-induced genes Tooth disease, Menkes disease, and Wilson and genes involved in cellular responses to viral disease. antigens, together with complement inhibitory Many of the genes responsible for those hy- molecules and genes involved in lipid meta- popigmentary disorders have been identified bolism and protein processing. Aggressive mas- and in general are involved with the intracellular tocytosis additionally shows deregulation of trafficking of proteins to LROs (including me- apoptosis and cell cycle-related genes, whereas lanosomes), in the transport of organelles to patients with indolent mastocytosis display in- the peripheries of the cell and in their transfer creased expression levels of adhesion-related to surrounding keratinocytes. Figure 2 outlines molecules (Teodosio et al. 2013). Sotos syn- the diagnostic decision tree for representative

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Melanocytes and Their Diseases

Congenital hypopigmentation disorders

Comorbidities? Systemic? Comorbidities? Ye s No Ye s No Ye s No

If bleeding, If deafness, Nevus Hermansky– Waardenburg depigmentosus Pudlak syndrome (incomplete syndrome (frontal gray depigmentation hair) and most common) If infection, Chediak– If megacolon Higashi and neural Piebaldism syndrome, disorder, (white forelock Griscelli Hirschsprung’s and ventral syndrome, disease type 2 leukoderma) or (white spots) Hermansky– Pudlak If neural syndrome disorders, type 2 Hypomelanosis of Ito Oculocutaneous (along Blaschko albinism or lines) Griscelli syndrome type 3

Figure 2. Diagnosis of congenital hypopigmentation disorders. Key elements for accurate diagnosis are size (systemic or localized), comorbidities, site of the involvement, and patterns/shapes of the lesions.

congenital hypopigmentation disorders, and we Acquired Hypopigmentation Disorders recommend that interested readers check the many references shown in the ESPCR webpage Acquired hypopigmentation disorders in- for further details and updates of genes associ- clude vitiligo, Sutton nevus, Vogt-Koyanagi- ated with congenital hypopigmentary diseases. Harada disease, malignancy-induced hypo- As recently reviewed, Hermansky-Pudlak syn- pigmentation (from melanoma and mycosis www.perspectivesinmedicine.org drome, characterized by oculocutaneous albin- fungoides), postinflammatory hypopigmen- ism, prolonged bleeding times, and pulmonary tation, chemical/drug-induced leukoderma, fibrosis, is triggered by syndromic dysgenesis senile leukoderma, and pityriasis alba. Most of specialized LROs including melanosomes, of these acquired hypopigmentation disorders platelet granules, synaptic vesicles, lytic gran- are associated with inflammation and a recent ules, Azurophil granules, and lamellar bodies study shows that TNF-a and IL-17 synergis- (Weiand Li 2013). Its responsible dysfunctional tically suppress pigmentation-related signaling proteins include the biogenesis of lysosome-re- and melanin production partly via MC1R lated organelles complex 1 (BLOC-1), BLOC-2, (Wang et al. 2013). Hypopigmentation is also BLOC-3, and AP-3. Forexample, the responsible related with other syndromes (such as ataxia gene for Hermansky-Pudlak syndrome type 7 is telangiectasia, Alezzandrini syndrome, Preus DTNBP1 (dysbindin), a component of BLOC-1 syndrome, Tietz syndrome, tuberous sclerosis, (Li et al. 2003). Hypomelanosis of Ito may be Rothmund–Thomson syndrome, and Werner derived from duplication of Xp11.3-p11.4 and syndrome) and infections (such as HIV, Han- random X-inactivation (Zou and Milunsky sen’s disease, Malassezia furfur, and syphilis). 2009). Vitiligo is discussed further below.

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Y. Yamaguchi and V.J. Hearing

Vogt–Koyanagi–Harada disease is a bilat- DSH, also called reticulate acropigmentation eral, chronic, diffuse granulomatous uveitis of Dohi, is a pigmentary of au- with poliosis, vitiligo, central nervous system, tosomal dominant inheritance and two groups and auditory signs. Many researchers, especially have reported that the causative gene is ADAR1 Yang’s group, have investigated the gene poly- (DSRAD; double-stranded RNA-specific adeno- morphisms of many factors including IL-17 sine deaminase) (Li et al. 2005; Suzuki et al. that are associated with Vogt–Koyanagi–Ha- 2005). Various types of XP are reviewed else- rada disease in a Chinese Han population where (DiGiovanna and Kraemer 2012), but (Shu et al. 2010) since Yakura et al. first reported mutations of DNA repair related genes after the HLA-D locus linkage (Yakura et al. 1976). UV-induced damage play key roles in the forma- The causative gene for ataxia telangiectasia is tion of XP. ATM (ataxia-telangiectasia mutated) localized at 11q22.3–23 (Ambrose and Gatti 2013). Vitiligo as a Representative of an Acquired Amiel et al. reported that mutations in MITF Hypopigmented Disorder result in Tietz syndrome (albinism-deafness) similar to Waardenberg syndrome type 2 Simple physical examination (lesions are de- (Amiel et al. 1998). Tuberous sclerosis results pigmented completely at the initiation phase, from dysregulation of mTOR signaling caused pigmented orifices of hair follicles are seen by mutations in tuberin and/or hamartin and at the recovering phase, and hyperpigmented Wataya-Kaneda et al. reported that angiofibro- ridges surrounded by the lesion are seen at mas can be treated with topical rapamycin oint- the stable/intractable phase) and/or present ment (Wataya-Kaneda et al. 2011). Although history (acquired depigmentation with or Werner syndrome is generally caused by muta- without autoimmune comorbidities) should tions in the WRN gene, a recent epigenetic be sensitive and specific enough for the correct study shows that aberrant DNA methylation diagnosis of vitiligo (Taieb and Picardo 2009), profiles result in premature aging diseases and which can sometimes be confused with (Heyn et al. 2013). other hypopigmented disorders (listed in Table 1 and see above). However, it may be difficult to differentiate vitiligo from nevus depigmen- Mixed Hyper-/Hypopigmentation tosus at childhood because depigmentation is Disorders not usually remarkable at infancy. Vitiligo can Congenital mixed hyper-/hypopigmentation be divided into two categories: generalized vit- disorders include , dys- iligo (wide distribution) and segmental vitiligo www.perspectivesinmedicine.org chromatosis symmetrica hereditaria (DSH), (confined to the dermatome). Typically, gener- and xeroderma pigmentosum (XP), and ac- alized vitiligo starts from the face and/or the quired hyper-/hypopigmentation disorders in- dorsal side of the hands, which are cosmeti- clude photoleukomelanoderma and drug-in- cally important part(s) of the body, and occurs duced mixed hyper-/hypopigmentation. mostly during adolescence/puberty. Comor- Incontinentia pigmenti, a rare X-linked bidities include other autoimmune diseases in- genodermatosis, commonly consists of 4 stages: cluding thyroid disease and pernicious anemia. inflammatory vesicular rash, verrucous lesions, The prevalence is approximately 0.5% with dif- linear or reticular hyperpigmentation, and fi- ferent studies estimating a prevalence rate of nally atrophic hypopigmented skin. Many in- 0.2%–0.9% (Nordlund 1997) and vitiligo is vestigators have reported that gene mutations the 18th commonest disease seen in Japanese responsible for incontinentia pigmenti occur clinics (Furue et al. 2011). The in NEMO (nuclear factor-kB essential modu- course of the disease appears to be unpredict- lator)/IKBKG (inhibitor of k light polypep- able; the skin lesions are often stable for more tide gene enhancer in B cells, kinase g), locat- than a year whereas others are slowly/rapidly ed at chromosome Xq28 (Fusco et al. 2012). progressive. The spontaneous healing rate is ap-

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Melanocytes and Their Diseases

proximately 10%. The impact of vitiligo on the MELANOMA—THE MALIGNANT patients’ quality of life may be higher in more MELANOCYTE pigmented populations and in young adults It is beyond the scope of this review to cover the based on the contrast of depigmented lesions topic of melanoma, the transformed melano- and their surrounding areas and the social ac- cyte, other than to say that it is the most lethal tivities, respectively. In general, socially active of all types of skin cancers and its incidence is patients tend to be eager to undergo any possi- growing at an alarming rate. A number of gene ble treatment options aiming for a cure, and loci have been characterized that are associated socially inactive patients are often untreated or with the process of malignant transformation, undertreated. growth, and metastasis of melanoma cells, and As summarized by Grimes (2005), the pres- these have been recently reviewed by Fisher’s ence of CD8þ T cells in close apposition to me- group (Tsao et al. 2012). Several melanoma sus- lanocytes suggests that the pathogenesis ceptibility genes are related with genes respon- of vitiligo is T cell mediated. The disease may sible for pigmentation disorders including XP also be antibody mediated in that vitiligo pa- and LEOPARD syndrome. We refer readers to tients frequently have antibodies to surface Hawryluk and Tsao (2014) for further informa- and cytoplasmic melanocyte antigens. In- tion about melanoma. Of note, the gene expres- creased cytokine levels, including IFN-g and sion profile of acral melanoma is dramatically TNF-a, have been detected in the skin of vitiligo different from the profiles of other types of mel- patients. Tacrolimus-induced repigmentation anoma (Curtin et al. 2005). Because the origin of vitiligo lesions is related with a reduction of melanocytes may be diverse depending on to normal of the elevated TNF-a in the lesional the site, UV-induced, non-UV-induced, acral, skin. and mucosal melanomas may need to be treated Many candidate genes/loci are thought to with different therapeutic regimens. Prelimi- be involved with the pathogenesis of vitiligo. nary data show that acral melanocytes appear Among them, Spritz’s group recently reported at rete ridges during embryogenesis, which may significant associations between generalized vi- be related with the dermoscopic patterns of the tiligo (from European-derived white ancestry) parallel ridge (instead of furrow) in acral mela- and SNPs (single-nucleotide polymorphisms) noma (data not shown). at many responsible loci using genome-wide association analyses. Most, if not all, of those genes are involved with regulation/function CONCLUDING REMARKS of the immune system. In addition to the www.perspectivesinmedicine.org NALP1 gene (Jin et al. 2007), those include Here we summarized recent discoveries of me- MHCI, MHCII, PTPN22, LPP, IL2RA, UBA- lanocyte biology from the aspects of basic and SH3A, C1QTNF6, RERE, GZMB (Jin et al. clinical science although space considerations 2010a), FOXP1, CCR6 (Jin et al. 2010b), do not allow us to provide a comprehensive OCA2-HERC2, MC1R, a region near TYR, overview of all of the important molecules in- IFIH1, CD80, CLNK, BACH2, SLA, CASP7, volved in melanogenesis. We recommend that CD44, IKZF4, SH2B3, and TOB2 (Jin et al. interested readers check the curated pigment 2012). The same group also reported the in- gene database of the ESPCR web page because volvement of NLRP1, a key regulator of the in- new pigment-related genes are being identified nate immune system, in the pathogenesis of vi- over time. That web site currently lists more tiligo (Levandowski et al. 2013). Although there than 350 genes associated with pigmentation is currently no single complete cure available to and is frequently updated and categorized ac- treat vitiligo (Oiso et al. 2013), these series of cording to the mechanisms of action of those studies may bring new approaches for therapy genes and associated pigmentary diseases. Fu- to vitiligo patients in the near future after care- ture studies of melanocytes will further eluci- ful clinical trials. date the mechanisms involved in the regulation

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of melanocyte development and heterogeneity, and positioning during melanosome biogenesis. J Cell by which hair graying and melanocyte senes- Biol 187: 247–264. DiGiovanna JJ, Kraemer KH. 2012. Shining a light on xero- cence occur, and disruptions of which cause derma pigmentosum. J Invest Dermatol 132: 785–796. most pigmentary disorders. It is our hope that Dumitrescu CE, Collins MT. 2008. McCune-Albright syn- further studies will lead to the development of drome. Orphanet J Rare Dis 3: 12. complete effective therapies for those disorders, Firestone AJ, WeingerJS, Maldonado M, Barlan K, Langston especially malignant melanoma. LD, O’Donnell M, Gelfand VI, Kapoor TM, Chen JK. 2012. Small-molecule inhibitors of the AAAþ ATPase motor cytoplasmic dynein. Nature 484: 125–129. ACKNOWLEDGMENTS Furue M, Yamazaki S, Jimbow K, Tsuchida T, Amagai M, Tanaka T, Matsunaga K, Muto M, Morita E, Akiyama M, This research was supported by the Intramural et al. 2011. 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Melanocytes and Their Diseases

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Melanocytes and Their Diseases

Yuji Yamaguchi and Vincent J. Hearing

Cold Spring Harb Perspect Med 2014; doi: 10.1101/cshperspect.a017046

Subject Collection The Skin and Its Diseases

Melanoma: Clinical Features and Genomic Modeling Cutaneous Squamous Carcinoma Insights Development in the Mouse Elena B. Hawryluk and Hensin Tsao Phillips Y. Huang and Allan Balmain Wound Healing and Skin Regeneration Natural and Sun-Induced Aging of Human Skin Makoto Takeo, Wendy Lee and Mayumi Ito Laure Rittié and Gary J. Fisher The Dermal Papilla: An Instructive Niche for Advanced Treatment for Basal Cell Carcinomas Epithelial Stem and Progenitor Cells in Scott X. Atwood, Ramon J. Whitson and Anthony E. Development and Regeneration of the Hair Follicle Oro Bruce A. Morgan Immunology and Skin in Health and Disease Epidermal Polarity Genes in Health and Disease Jillian M. Richmond and John E. Harris Frederik Tellkamp, Susanne Vorhagen and Carien M. Niessen Desmosomes: Regulators of Cellular Signaling Induced Pluripotent Stem Cells in Dermatology: and Adhesion in Epidermal Health and Disease Potentials, Advances, and Limitations Jodi L. Johnson, Nicole A. Najor and Kathleen J. Ganna Bilousova and Dennis R. Roop Green Markers of Epidermal Stem Cell Subpopulations The Genetics of Human Skin Disease in Adult Mammalian Skin Gina M. DeStefano and Angela M. Christiano Kai Kretzschmar and Fiona M. Watt Psoriasis p53/p63/p73 in the Epidermis in Health and Paola Di Meglio, Federica Villanova and Frank O. Disease Nestle Vladimir A. Botchkarev and Elsa R. Flores Cell Therapy in Dermatology Diversification and Specialization of Touch Gabriela Petrof, Alya Abdul-Wahab and John A. Receptors in Skin McGrath David M. Owens and Ellen A. Lumpkin

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