Interplay of Light, Melatonin, and Circadian Genes in Skin Pigmentation Regulation

Abstract

AbstractHighlightsCircadian pigmentation of tadpoles in vivo is mainly driven by melatoninLight and melatonin differentially regulate proliferationMelatonin mimics the expression of circadian core genes in the dark phaseDeregulation of the circadian rhythm inhibits melanin synthesisCircadian regulation of skin pigmentation is essential for thermoregulation, UV protection, and synchronization of skin cell renewal. This regulation involves both cell-autonomous photic responses and non-cell-autonomous hormonal control, particularly through melatonin produced in a light-sensitive manner. Photosensitive opsins, cryptochromes, and melatonin regulate circadian rhythms in skin pigment cells. We studied light/dark cycles and melatonin coordination in melanin synthesis and cell proliferation ofXenopus laevismelanophores.In vivo, tadpole pigmentation shows robust circadian regulation mainly hormone-driven, in that isolated melanophores respond strongly to melatonin but only slightly to light. Melanophore proliferation is faster in the dark and slower with melatonin compared to a 12/12 light/dark cycle. Expression of circadian core genes (clock, bmal1, per1, per2, per3, cry1, cry2, and cry4) in melatonin-treated cells during the light phase mimics dark phase expression. Individual Cry overexpression did not affect melanisation or cell proliferation, likely due to functional redundancy. Melanin synthesis was inhibited by circadian cycle deregulation through: a) pharmacological inhibition of Cry1 and Cry2 degradation with KL001, b) continuous light or dark conditions, and c) melatonin treatment. Our findings suggest that circadian cycle regulation, rather than proliferative capacity, alters melanisation of melanophores.SignificanceCircadian rhythms are a highly conserved phenomenon in nature. In vertebrates, the modification of skin pigmentation and epidermal cell renewal in response to the environmental light-dark cycle are crucial physiological adaptations that serve various purposes, including thermoregulation, reducing ultraviolet damage, and regulating skin stem cell proliferation. Our observations indicate that,in vivo, the circadian regulation of skin pigmentation is more influenced by cycling-melatonin levels than light/dark. The deregulation of the circadian cell cycle through various mechanisms all inhibited melanisation while cell proliferation was increased or reduced, suggesting that proliferation and melanisation are mechanistically dissociated responses.Graphical Abstract