Melanocyte Biology

Melanocytes are specialized pigment-producing cells that reside in the eyes, hair follicles and skin. They develop during embryogenesis as melanocyte precursor cells that originate from the neural crest and differentiate into mature melanocytes via a series of steps which activate the transcription factors MITF (microphthalmia-associated transcription factor) and Pax3 (paired box 3). MITF is a key regulator of melanocyte differentiation through its control of melanin synthesis genes TYR (tyrosinase), TRP1 (tyrosinase-related protein 1) and TRP2 (tyrosinase-related protein 2) (1).

Melanin production

Pigmentation signaling regulates melanin production in melanocytes (1). Eumelanin is the form of melanin associated with brown to black pigmentation while phenomelanin is the form associated with yellow to red pigmentation. MITF-mediated melanin production is influenced by a combination of regulation of MITF expression and post-translational MITF modification.

The cyclic adenosine 3,5-monophosphate (cAMP) pathway exerts the greatest control on melanin production. Activated by α-MSH (melanocyte stimulating hormone, MSH) binding to MCR1 (melanocortin 1 receptor), cAMP activates PKA (protein kinase A) which in turn phosphorylates and activates CREB (cyclic AMP response element binding protein), upregulating MITF expression and increasing MITF production over the course of hours. Incidentally, UV radiation exposure stimulates expression of the α-MSH precursor Proopiomelanocortin (POMC), suggesting involvement of the cAMP pathway in skin adaptations due to UV exposure.

Wingless-related integration site (Wnt) signaling, specifically Wnt1 and Wnt3A working with β-catenin and T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, is another factor in regulating MITF expression. Wnt signaling is particularly important in promoting initial melanocyte development.

SCF (stem cell factor) and its receptor c-KIT increase MITF activity through short lived ERK1/ERK1 (extracellular signal regulated kinase 1/2) mediated phosphorylation that also induces MITF degradation.

Melatonin influence

Melatonin, a hormone synthesized primarily by the pineal gland and a regulator of circadian rhythms, has been shown to influence melanocyte proliferation and melanin production (2). It does so by acting through MTNR1A (melatonin receptor 1A, MT1) and MTNR1B (melatonin receptor 1B, MT2) G-protein coupled receptors to inhibit MITF production, although recent evidence suggests that these effects are variable and are influenced by the tissue type and signaling environment in addition to other factors.

Systemic circulating melatonin is degraded in the liver, primarily via melatonin degradation I pathway, an indolic pathway which produces 6-hydroxymelatonin – a metabolite that is further sulfated and secreted in the urine (3,4). Melatonin produced locally in epidermal skin cells is additionally degraded by melatonin degradation II pathway, another indolic pathway that produces 5-methoxytryptamine (5-MT). As well as melatonin degradation III pathway, a kynuric pathway that produces N-acetyl-N-formyl-5-methoxykynurenamine (AFMK). Along with melatonin, AFMK has been shown to provide protection against UV radiation.

Combined, the pathways are known as the superpathway of melatonin degradation (5). Production levels of the different metabolites within epidermal skin cells have been shown to differ based on age, gender and race (4). All three major metabolites, similar to melatonin itself, appear to inhibit tyrosinase activity and melanocyte proliferation.

References

1. D'Mello SA, Finlay GJ, Baguley BC, Askarian-Amiri ME. Int J Mol Sci. 2016;17(7):1144. doi: 10.3390/ijms17071144.
2. Sevilla A, Chéret J, Slominski RM, Slominski AT, Paus R. J Pineal Res. 2022;72(3):e12790. doi: 10.1111/jpi.12790.
3. Slominski AT, Semak I, Fischer TW, Kim T, Kleszczyński K, et al. Exp Dermatol. 2017;26(7):563–568. doi: 10.1111/exd.13208.
4. Kim T, Lin Z, Tidwell WJ, Li W, Slominski AT. Mol Cell Endocrinol. 2015;404:1–8. doi: 10.1016/j.mce.2014.07.024.
5. MetaCyc https://biocyc.org/pathway?id=PWY-6402 (accessed June 12, 2024)