From neural crest cells to melanocytes: cellular plasticity during development and beyond

Abstract

Here, we review melanocyte development and how the embryonic melanoblast, although specified to become a melanocyte, is prone to cellular plasticity and is not fully committed to the melanocyte lineage. Even fully differentiated and pigment-producing melanocytes do not always have a stable phenotype. The gradual lineage restriction of neural crest cells toward the melanocyte lineage is determined by both cell-intrinsic and extracellular signals in which differentiation and pathfinding ability reciprocally influence each other. These signals are leveraged by subtle differences in timing and axial positioning. The most extensively studied migration route is the dorsolateral path between the dermomyotome and the prospective epidermis, restricted to melanoblasts. In addition, the embryonic origin of the skin dermis through which neural crest derivatives migrate may also affect the segregation between melanogenic and neurogenic cells in embryos. It is widely accepted that, irrespective of the model organism studied, the immediate precursor of both melanoblast and neurogenic populations is a glial-melanogenic bipotent progenitor. Upon exposure to different conditions, melanoblasts may differentiate into other neural crest-derived lineages such as neuronal cells and vice versa. Key factors that regulate melanoblast migration and patterning will regulate melanocyte homeostasis during different stages of hair cycling in postnatal hair follicles.

Keywords: Cellular plasticity; EMT; Melanocytes; Migration; Neural crest; ZEB proteins.

Fig. 1

Neural crest specification and delamination. Neuroectodermal patterning is a very dynamic developmental program in which Notch signaling and secreted ligands such as BMP, WNT and FGF will specify the posterior neural border and the neural crest arising at the neural folds upon closure of the neural tube. During different stages, different genes are expressed that mark the neural plate border and premigratory and dispersed neural crest cells

Fig. 2

Model for mouse melanoblast migration. Melanocytes differentiating from melanoblast cells in the body trunk arise via the dorsolateral migration route between the ectoderm and dermomyotome. Neurogenic populations differentiating from ventrally migrating neural crest cells. In addition, ventrally migrating neural crest cells give rise to numerous other lineages, whereas the dorsolateral pathway is restricted to melanoblasts only (see text). MSA migratory staging area

Fig. 3

New hypothetical model for avian neural crest migration. Melanocytes differentiating from melanoblast cells arising via the dorsolateral migration route migrate through and populate the developing dermis derived from somites (dermomyotome, DM), whereas melanocytes differentiating from ventrally migrating Schwann cell precursors (SCPs) are restricted to skin composed of dermis originating from the lateral plate mesoderm (LPM). The differential mesodermal patterning of the skin is delineated by the ectodermal notch. In addition to SCPs, ventrally migrating neural crest cells give rise to numerous other lineages, whereas the dorsolateral pathway is restricted to melanoblasts only (see text). No notochord (derived from paraxial mesoderm), Nt neural tube, MSA migratory staging area, S sclerotome, DM dermomyotome (somite derived from paraxial mesoderm), LPM lateral plate mesoderm, SCP Schwann cell precursor

Fig. 4

Melanoblast development. a Schematic overview of different stages of melanoblast migration and development in mouse embryos. Details are described within the text. MSA migratory staging area. b Melanoblasts that reach the epidermis and the hair follicles will be segregated into distinct populations during hair follicle morphogenesis. Epidermal interfollicular melanocytes are responsible for skin pigmentation, while hair follicle melanocytes synthesize pigment for the hair

Fig. 5

Sources of differentiated melanocytes. During embryonic development, melanoblast originate from a bipotent melanoblast/glial precursor cell. Melanoblasts that reach developing hair follicles will be segregated into two distinct and physically separated populations during hair follicle morphogenesis. One population will localize in the hair follicle bulb, where they differentiate into mature melanocytes and immediately contribute to hair pigmentation during the first hair cycle. The other population consists of melanocyte stem cells that reside within a specialized stem cell niche, referred to as the hair follicle bulge, and serve as reservoir to replenish the cycling hair follicles with new melanocytes. Schwann cell precursor cells (SCP) may also differentiate into mature melanocytes in vitro or after wounding in vivo. While the relative contribution of SCPs to embryonic and physiological melanocytes in mice remains to be elucidated, in chick embryos SCPs contribute to melanocytes from early embryonic development

Fig. 6

Sun tanning response. Upon sunlight exposure, the upper layers of epidermis become exposed to UV radiation. Several signaling cascades following p53 activation are initiated. These pathways include the secretion of growth factors such as a-MSH, FGF2, KITL and EDN1, which in turn will bind their cognate receptors on melanocytes and activate a differentiation program mediated by PAX3 and MITF. MITF is a main activator of genes involved in pigment synthesis, melanosome generation and trafficking. In the absence of sunlight and UV exposure, TGF-β secreted from the keratinocytes keep the melanocytes in a quiescent state

Fig. 7

Schematic overview of mouse hair cycle. Description in text (DP dermal papilla)

Fig. 8

Overview of melanocyte stem cell quiescence and activation. Schematic overview of autocrine and paracrine signaling factors affecting melanocyte stem cell differentiation as described in the text. UPP upper permanent portion, LPP lower permanent portion, TP transient portion, Diff. differentiated

Fig. 9

Possible sources of melanocyte stem cells that replenish interfollicular melanocytes. MSC melanocyte stem cells. Interfollicular melanocytes may originate from bulge melanocyte stem cells after upward migration, an epidermal melanocyte stem cell, a dermal melanocyte stem cell or a neural crest-like stem cell

Fig. 10

Disorders and syndromes associated with melanocyte dysfunction. Piebaldism photograph courtesy of Fleischman [99]