Let’s stick together

Abstract

If there is one defining characteristic of a melanocyte it is the melanosome, the organelle dedicated to the synthesis and containment of melanin. Once a melanosome is made, the question is what happens next. For neural crest-derived melanocytes, as opposed to the retinal pigment epithelium, the ultimate destination of melanosomes is likely to be surrounding keratinocytes where they will function to prevent UV-induced DNA damage. Over the years, a lot has been discovered about the process of melanosome genesis and the enzymes involved in the manufacture of pigment. More recently the molecular mechanisms that direct melansomes to the cell periphery and along their dendritic processes have been deciphered, though there is still much to learn. Yet remarkably, the final step in the journey, how melanosomes are transferred to keratinocytes and what happens once transfer has taken place remains a mystery. Despite the efforts of several laboratories, no clear underlying mechanism has been described. What is clear though is that in the natural context in the skin, intimate contact between the melanocyte and surrounding keratinocytes is likely to be critical. In this issue the paper from Joshi et al., reveals a feature of the consequences of melanosome transfer to keratinocytes; the release of calcium from an intracellular source within the keratinocyte. The results further suggest that there are specific melanocyte membrane-associated proteins that are necessary for the Ca2+ signal. The paper is interesting in that it raises several interesting questions. First, what is the source of the intracellular calcium released on uptake of the melanosome? Does it arise from Ca2+ stores within the keratinocyte, or, given the ability of melanin to bind calcium as described in a recent paper in this journal from the John Simon lab, is it released from within the transferred melansome? And second, what is the role of the released Ca2+? One possibility is that it primes the keratinocyte to mobilise its intra-cellular transport machinery to correctly position the incoming melansome. Alternatively, the calcium release detected by Joshi et al could potentially be a component of the hypothesized feedback mechanism by which keratinocytes would tell melanocytes that a melanosome has been received. Whatever the answers to these questions, monitoring Ca2+ release within keratinocytes will represent a useful tool to those wishing to identify the mechanism underlying melanosome transfer. The close contact between melanocytes and keratinocytes underpins melanosome transfer, but the ability of melanocytes and keratinocytes to stick together has become a focus of research on vitiligo, a complex disease characterised by loss of epidermal and follicular melanocytes. Several models have been proposed to explain the various features of melanocytes, many of which are covered in the reviews on vitiligo genetics by Rich Spritz in the last issue of Pigment Cell Research and in the review from Westerhof and d’Ischia in this issue. It is clear that one feature of melanocyte loss in vitiligo is their destruction by an auto-immune response. Precisely what triggers the auto-immunity isn’t well defined, but both Westerhof and d’Ischia, as well as Namazi, provide a number of suggestions based on the possibility that modification of melanocyte proteins would lead to the production of neo-antigens not normally encountered by the immune system. The presence of neo-antigens would then lead to a bystander effect and the potential for an auto-immune based reaction against melanocytes. However, for neo-antigens to be seen by the immune system would require their release from within melanocytes. Here, accumulating evidence suggest that the melanocytes from vitiligo prone individuals may be more sensitive to stress. In other words, the threshold for stress-induced damage to melanocytes in vitiligo patients would be substantially lower than in normal individuals. One way in which stress might affect melanocytes is in their ability to interact with surrounding keratinocytes, and indeed stress signalling is known to down-regulate the key cell–cell adhesion molecule E-cadherin. In the paper from Cario-André et al., the response of melanocytes in skin reconstructs to various stressors is examined. In agreement with the stress-sensitivity hypothesis, the melanocytes derived from non-lesional skin from individuals with vitiligo behaved differently from melanocytes from non-affected individuals. The defects were enhanced if the melanocytes from vitiligo individuals were combined with keratinocytes from non-lesional skin. The results presented, suggest that there may well be a degree of systemic stress-hypersensitivity in the epidermal melanocyte–keratinocyte interactions in individuals with vitiligo.