The melanocyte lineage in development and disease

Abstract

Melanocyte development provides an excellent model for studying more complex developmental processes. Melanocytes have an apparently simple aetiology, differentiating from the neural crest and migrating through the developing embryo to specific locations within the skin and hair follicles, and to other sites in the body. The study of pigmentation mutations in the mouse provided the initial key to identifying the genes and proteins involved in melanocyte development. In addition, work on chicken has provided important embryological and molecular insights, whereas studies in zebrafish have allowed live imaging as well as genetic and transgenic approaches. This cross-species approach is powerful and, as we review here, has resulted in a detailed understanding of melanocyte development and differentiation, melanocyte stem cells and the role of the melanocyte lineage in diseases such as melanoma.

Keywords: MITF; Melanoma; Neural crest; Stem cells.

Fig. 1.

An overview of melanocyte development. (A) In mammals, melanoblasts are specified from neural crest cells (NCCs) via a SOX10-positive melanoblast/glial bipotent progenitor. SOX10 expression remains switched on in both of these lineages. Melanoblasts subsequently are specified and acquire MITF, DCT and KIT expression. After colonising the developing embryonic hair follicles, some melanoblasts differentiate into melanocytes and produce the pigment (melanin) that colours the first hair cycle. A subset of melanoblasts dedifferentiate (losing MITF and KIT expression but not DCT) to form melanocyte stem cells in the hair follicle bulge that replenish the differentiated melanocytes via a rapidly proliferating transit-amplifying cell in the subsequent hair cycles. The image on the far right is of a transgenic mouse embryo expressing lacZ under control of the melanoblast promoter Dct. X-Gal staining reveals blue-stained melanoblasts, in particular those migrating from the cervical neural crest and in the head. Also stained are the telencephalon, the dorsal root ganglia (DRG) and the retinal pigmented epithelium of the eye. (B) In zebrafish, there are distinct embryonic and adult pigmentation patterns, as illustrated in the images on the far right. The melanoblasts that form both these patterns originate from a SOX10-positive neural crest-derived progenitor. The embryonic pattern is formed by melanocytes that develop directly from this progenitor via an MITF+ melanoblast. The melanoblasts that form the adult pattern are derived from a melanocyte stem cell population that resides at the dorsal route ganglia (DRG) and is specified by an ERB- and KIT-dependent pathway in the embryo.

Fig. 2.

Development of the melanocyte lineage. (A) In mouse and chick embryos, early melanoblasts are derived from the neural crest and migrate dorsolaterally through the dermis between the somites and the developing epidermis. At later stages, they become epidermal, and a second wave is thought to differentiate from Schwann cell precursors associated with developing nerves, contributing to the adult melanocytes of the trunk, head and developing limbs. It is not clear whether the late population intercalates with or replaces the early population. (B) In zebrafish embryos, melanocytes migrate dorsolaterally and along nerves ventrally (purple) to form the embryonic pattern. Melanocyte stem cells (MSCs) are located at the DRG (marked by asterisk). Following metamorphosis or melanocyte ablation of the embryonic pattern, zebrafish glial-pigment cell progenitors proliferate and migrate along nerves to form the adult melanocyte stripes. MSCs specified in the developing embryo are the proposed source of metamorphic melanocytes of the adult. Adapted from Adameyko et al. (2009); Dooley et al. (2013); Dupin and Sommer (2012). NT, neural tube; N, notochord; dm, dermamyotome; DRG, dorsal root ganglia; S, somite; D, dorsal; V, ventral; L, lateral; M, medial.

Fig. 3.

Melanocyte stem cells in ageing and disease. (A) Melanocyte stem cells (MSCs; pink circles) associated with the hair follicle provide pigmented cells to the growing hair. These follicular MSCs reside in the bulge region of the hair follicle and are supported in a niche by hair follicle stem cells (blue). Differentiated melanocytes (black) reside at the bulb to pigment the growing hair. Aging or genotoxicity lead to the ectopic differentiation of MSCs in the follicular niche, resulting in a loss of the MSC pool and hence loss of pigmentation of the hair. This gives rise to grey hair, as illustrated in the image of a mouse (far right), in which genotoxic stress caused by ionizing radiation has induced hair greying [image courtesy of Emi Nishimura (Tokyo Medical and Dental University, Tokyo, Japan)]. The follicular MSCs also act as a reservoir for epidermal melanocytes in vitiligo patients, such that melanocytes from the MSC population migrate (indicated by red arrows) to the skin. This results in the patches of pigmented skin associated with hair follicles that are observed in vitiligo patients, as illustrated in the image on the right. [Image from Grichnik (2008) with permission.] (B) MSCs (pink circles) have also been identified in the sweat glands of volar skin and can contribute to the epidermal melanocyte population (black). The sweat gland can also provide a niche for melanoma-initiating cells (black), which explains the ‘parallel ridge pattern’ of acral melanoma cells at the sweat gland [illustrated in the image on the far right; image from Saida et al. (2002) with permission]. Schematic images adapted from Nishimura (2011); Zabierowski et al. (2011).