Melanocyte lineage dynamics in development, growth and disease

Abstract

Melanocytes evolved to produce the melanin that gives colour to our hair, eyes and skin. The melanocyte lineage also gives rise to melanoma, the most lethal form of skin cancer. The melanocyte lineage differentiates from neural crest cells during development, and most melanocytes reside in the skin and hair, where they are replenished by melanocyte stem cells. Because the molecular mechanisms necessary for melanocyte specification, migration, proliferation and differentiation are co-opted during melanoma initiation and progression, studying melanocyte development is directly relevant to human disease. Here, through the lens of advances in cellular omic and genomic technologies, we review the latest findings in melanocyte development and differentiation, and how these developmental pathways become dysregulated in disease.

Keywords: Genomics; MITF; Melanocyte stem cells; Melanocytes; Melanoma; Multi-omics; Neural crest; Pigmentary disease; Pigmentation; Schwann cell precursor; Transcriptomics; scRNA-sequencing.

Fig. 1.

Melanocyte origins in development. (A) Neural crest cells (NCCs) are stem-like cells that generate a multitude of cell types, including derivatives in the cranial, vagal and trunk regions of the embryo. Cranial neural crest derivatives include facial ectomesenchyme (facial bones and cartilages), sensory nerves and facial dermis. Cardiac neural crest derivatives include pericytes and smooth muscle cells (SMCs). Vagal neural crest and trunk neural crest derivatives are similar and include different types of neurons (motor, sensory and enteric) and glia. (B) Upon induction, NCCs express a set of well-defined markers. The same markers are expressed, in mouse, later in development by the axon-associated SCPs together with the multipotency ‘hub’ markers (Sox8, Itg4, Ednrb and Serpine2) that keep the SCPs in a multipotent state primed for differentiation. The key event in melanocyte differentiation is the expression of the melanocyte-inducing transcription factor (Mitf), which triggers the expression of the Mitf-target genes involved in the synthesis of melanin and/or the formation of the melanosomes. (C) In mouse, bird and zebrafish experimental models, skin melanoblasts and melanocytes originate early in development from migrating NCCs (top) and later from progenitors associated with peripheral nerves (bottom). D, dorsal; DRG, dorsal root ganglion; L, lateral; McSC, melanocyte stem cell; Nc, notochord; V, ventral.

Fig. 2.

Melanocyte stem cell populations. (A) Melanocyte stem cells (McSCs) are found in a variety of locations in the mammalian skin, including in the hair follicle in both mouse and human. Each hair follicle is a tube-like structure that supports a single hair and goes through cycles of growth. Each cycle consists of three phases: telogen (resting phase), anagen (a proliferative phase) and catagen (transition stage). McSCs can be detected in the hair bulge area and in the hair germ (HG) during the telogen phase. McSCs in HG go through a transit amplifying-like stage in early anagen, and contribute to both differentiated melanocytes and renewal of McSCs in both compartments with each hair cycle (Sun et al., 2023). Hair follicle McSCs can also contribute to epidermal melanocytes (Chou et al., 2013). Fully differentiated melanocytes in the hair bulb contribute to hair coloration during late anagen before dying during catagen. Moreover, McSCs can be found in the sweat glands in volar skin (palms and soles), and, potentially, melanocytes could originate from dermal stem cells in the human dermis. (B) Recently, three cell states of melanocytic cells, including pigmented and dendritic cells, and two populations of undifferentiated cells (represented as purple cells in the schematic) have been described in the interfollicular regions of human skin. (C) In zebrafish, McSCs are associated with the site of the dorsal root ganglia (DRG) and transiently express tfap2b during establishment in the niche. These tfap2b⁺ cells reside in the McSC niche and lineage tracing studies demonstrate that they can generate all three pigment cell types and nerve-associated cells in the adult animal. APM, arrector pili muscle; MITF-M, microphtalmia-associated transcription factor (melanocyte-inducing transcription factor)-M; NT, neural tube; NCSC, neural crest stem cells.