Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press 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 melanocytes are distributed not only in the epidermis and in hair 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- melanin pigments in unique membrane-bound organelles termed melanosomes, 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 melanosome structure, and proteins required for their trafficking and distribution. Many genes are involved in regulating pigmentation at various levels, and mutations in many of them cause pigmentary disorders, which can be classified into three types: hyperpigmen- tation (including melasma), hypopigmentation (including oculocutaneous albinism [OCA]), and mixed hyper-/hypopigmentation (including dyschromatosis symmetrica hereditaria). We briefly review vitiligo as a representative of an acquired hypopigmentation disorder. igments that determine human skin 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, melanins play key roles similar to lysosomes 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 (lysosome-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 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press 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 melanocyte 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 hyperpigmentation, 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 depigmentation. 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 2 Cite this article as Cold Spring Harb Perspect Med 2014;4:a017046 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press 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 Chromosome lentiginosis associated noncutaneous 4q21.1-q22.3 abnormalities LEOPARD Multiple lentigines, congenital PTPN11 Protein tyrosine phosphatase, syndrome cardiac abnormalities, ocular nonreceptor type 11 hypertelorism, and retardation of growth Carney complex 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 Nevus cell nevus, Spitz nevus, Nevus spilus, blue nevus, nevus Ohta, dermal melanosis, 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/lentigo, 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