What is a vertebrate pigment cell?

The international pigment cell research community lost one of its pioneers and pillars with the passing away of Professor Joseph T. Bagnara on October 2, 2016. Joe, as we, his students who became his friends, called him, obtained his Ph.D. in 1956 from the State University of Iowa (now known as University of Iowa). He spent his entire career at the University of Arizona, rising through the ranks to Professor and Chairman of the Department of General Biology. In 1992, he became Professor Emeritus. He rightly merits to be called the father of comparative pigment cell biology, as he focused most of his research on investigating the regulation of color change in different amphibians. He was a hard-core embryologist, zoologist, and endocrinologist. Joe taught the Embryology courses at the University of Arizona, and his Embryology text book was used by many professors in different universities. He was a scholar with a vision who desired to connect with other scientists internationally. He was twice a Fulbright Research Scholar, which provided him with the opportunity to do research in the Laboratoire d'Embryologie, Faculté des Sciences, Université de Paris, Paris, France, and later at the Stazione Zoologica di Napoli in Italy. He pioneered the research on the role of the pineal gland in regulating skin lightening and the identification of the different types of pigment cells in amphibians. He had a multidisciplinary approach to his research, using in vivo experiments, organ and tissue culture, electron microscopy as well as biochemistry to demonstrate the effects of different hormones and the role of different chromatophores in regulating rapid color changes in frogs. Many of his publications are classics in the pigment cell research literature. He collaborated with his colleagues at the University of Arizona, and also with many pigment cell researchers in Europe and Japan. Joe cherished his role as a teacher and mentor. He was always proud of his mentees and their achievements. On his retirement party, which was held in 1995 during the annual meeting of the PanAmerican Society for Pigment Cell Research in Kansas City, Kansas, his former students gathered to celebrate his scientific achievements. The group included Dr. Sally K. Frost-Mason, who was President of the PanAmerican Society for Pigment Cell Research and until recently the President of the University of Iowa, and John Taylor, who was Professor at Wayne State University in Detroit, Michigan. Joe should be acknowledged for founding, in 1987, the journal Pigment Cell Research (now Pigment Cell and Melanoma Research) and for serving as its first editor-in-chief. He was very fond and proud of this personal project, and we are grateful that he gave us this medium to communicate our science and expand the breadth of our specialty. Joe also played a major role in establishing the International Federation for Pigment Cell Societies and is one of the founders of the PanAmerican Society for Pigment Cell Research, which was conceived during the International Pigment Cell meeting in Tucson, Arizona, in 1986. Joe won many prestigious international and national awards, including the Myron Gordon Award from the IFPCS, and the Career Achievement Award from PASPCR. Joe wrote his autobiography “Unfinished Business: a Biologist in the Latter Half of the 20th Century,” which is a “must read” for all pigment cell researchers, as he narrates the history not only of his own career and travels but also of the evolution of pigment cell research worldwide and the establishment of the International Federation of Pigment Cell Societies. Those of us who had the honor and privilege to know Joe personally remember him not only as a kind mentor but mostly as a friend who remained in touch with us and always provided words of encouragement and support. On a personal note, thanks to Joe, I joined the Department of Dermatology at the University of Cincinnati in 1985 after graduating with a Ph.D. from the University of Arizona. He was the one who introduced me to James Nordlund, M.D., the Chairman of the department and my postdoctoral mentor at the time. Joe enjoyed life, loved the wilderness, was an avid athlete, and cared for his students and friends without limits. He was proud to know several languages and to have international friends and colleagues. He inspired us to work hard yet enjoy life to the fullest. “If I have seen further it is by standing on the shoulders of giants” (Isaac Newton). Mentors are persons who help shape our lives without molding us necessarily in their image. Joe, you are gone, but your legacy lives in all of us who knew you. Fond memories always remain, and we strive to pass the torch to our own students and mentees.

testing the pigment-forming potency of various portions of mouse embryos of a potentially pigmented (black) strain, evidence was obtained which suggested that the migratory pigment-forming cells, the melanophores, take their origin from the neural crest, as in other vertebrates, e.g., amphibians and birds.The results of grafting a variety of embryonic mouse tissues, such as skin ectoderm plus the underlying mesoderm, somites with and without the adjacent neural tube, limb buds and prospective limb buds, from various body levels, showed

Over the past 5 years Vince Hearing has transformed Pigment Cell Research into a journal with an increasingly wide audience, publishing papers with ever higher quality that is reflected in the steadily increasing impact factor. He deserves the thanks of the entire pigment cell community for his outstanding efforts. As the incoming editor, I intend to continue his work in trying to improve the journal and to expand its audience, while at the same time serving the interests of the entire pigment cell research community and societies. As such the scope of the journal remains unchanged: the publication of papers relevant to all aspects of pigment cell research, including melanin chemistry, development, cell and molecular biology as well as pigment cell-related diseases such as vitiligo and melanoma. The long-term goal is that Pigment Cell Research will become the first choice for publication of many papers that currently go elsewhere. The major criteria for publication remains good quality, well controlled science relevant to pigment cell biology. As the melanocyte field is relatively small, there is a limit to the number of papers generated by the field as well as to how well read, and cited, papers published in Pigment Cell Research may be. This limit may be expanded if more people have access to the journal. For that reason reviews are now freely available online and papers will be published ‘online early’ ahead of appearing in the print issue to avoid delays arising from the bi-monthly publication schedule. Readership may further be increased if the pigment cell field expands. Indeed, recruitment of new members to the pigment cell community is also vital if research into melanocytes and related pigment cell types is to maintain a strong base and remain a vibrant and dynamic field. Pigment Cell Research has historically published few papers related to melanoma. Since the melanoma field is large, publishing papers specifically related to the genetics, molecular and cell biology of the disease, and consequently gaining readership in that area, will be important for the future of this journal. Hopefully this aim will be realised through the efforts of the melanoma specialists on the revised editorial board and the publication of a series of melanoma-related reviews. After all, melanoma proliferation and metastasis is underpinned by the subversion of genes implicated in normal regulation of melanocyte development. By attracting papers from both fields, Pigment Cell Research should stimulate research and provide a forum for the exchange of ideas between those seeking to understand and combat melanoma and those engaged in trying to understand the fundamental questions concerning the developmental pathways leading to mature pigment cells. Although my research interests extend to the basic mechanisms of how genes are regulated and I therefore mix with researchers from a variety of fields, the more I have become immersed in pigment cell biology, the more I appreciate the individuals that make up the pigment cell research community. For those I interact with through collaborations or at meetings, I feel it would be difficult to find a nicer bunch of people so willing to share ideas and reagents without reservation, and to collaborate in the spirit of friendship rather than outright competition at all costs. It seems to me that at this level, the ideals of science that seem sometimes to have been lost in some other fields are upheld within the pigment cell community and should be encouraged and preserved. Finally, there are also some changes in the presentation of the journal: a new format, and a new colour cover for each issue chosen from images provided by members of the pigment cell community. These are more than cosmetic. In providing a visually exciting image on the outside, I hope to entice more of you to look inside. In changing the format, I hope that readers and authors will feel that this is a modern and high quality publication. Some of the more attentive among you may also have noticed a change in citation format, from numbered to author-date. This is a personal whim, based on my own desire as a reader and a referee to have some idea as to which papers have been cited without having to resort to the reference list, as well as the painful experience of having to renumber all citations each time I have to revise my own manuscripts. The cover image for this month comes from Randy Morrison and shows a Madagascan chameleon. Chameleons have at least five different pigment cell types, symbolising the broad interests of the pigment cell community, while the dramatic colour changes displayed by male chameleons reflect the new style of the journal as well as the change of editor.

Animal pigment pattern: An integrative model system for studying the development, evolution, and regeneration of form

In vertebrates, melanins produced in specialized pigment cells are required for visual acuity, camouflage, sexual display and protection from ultra violet (UV) radiation. There are three pigment cell types that are classified based on their distinct embryonic origins. Retinal pigment epithelium (RPE) cells originate from the outer layer of the optic cup. Pigment cells of the pineal organ are formed from the developing diencephalon. Melanocytes are derived from the neural crest unique to vertebrate embryos. Some of these pigment cells also play roles that are independent of the activity of tyrosinase, the key melanogenesis enzyme, or melanin: production of substrate(s) for catecholamine synthesis, maintenance of endolymph composition in the cochlea, maintenance of photoreceptor cells in the retina and retinoid metabolism essential for the visual cycle. To deduce the evolutionary origins of vertebrate pigment cells and a possible archetypal genetic circuitry, which may have been modified and utilized to generate multiple pigment cell types, comparison of developmental mechanisms of pigment cells between vertebrates and closely related invertebrate ascidians are proposed to provide useful information. The tadpole-type larva of ascidians possesses two melanin-containing pigment cells, termed the otolith and ocellus pigment cells, in the brain that are believed to be required for photo- and geotactic responses during swimming. In this review, current knowledge on the development of the two ascidian pigment cells is summarized, i.e. complete cell lineage, structure and expression of genes encoding two melanogenesis enzymes, and molecular developmental mechanisms involving BMP-CHORDIN antagonism, and possible evolutionary relationships between ascidian and vertebrate pigment cells are discussed.

Mitf encodes a basic helix-loop-helix transcription factor that plays an essential role in the differentiation of the retinal pigmented epithelium (RPE) and neural crest-derived melanocytes. As cells containing melanogenic enzymes (TRP2) are found in Mitf mouse mutants, it is not clear whether Mitf is a downstream factor or a master regulator of melanocyte differentiation. To further study the role of Mitf in committing cells to the melanocyte lineage, we express Mitf in the cultured quail neuroretina cells. This leads to the induction of two types of pigmented cells: neural crest-derived melanocytes, according to their dendritic morphology, physiology, and gene expression pattern are observed together with pigmented epithelial RPE-like cells. The expression of Mitf is lower in pigmented epithelial RPE-like cells than in neural crest-derived melanocytes. Accordingly, overexpression of Mitf in cultured quail RPE causes cells to develop into neural crest-like pigmented cells. Thus, Mitf is sufficient for the proper differentiation of crest-like pigmented cells from retinal cells and its expression level may determine the type of pigment cell induced.

Four types of mesoderm cells (pigment cells, blastocoelar cells, coelomic pouch cells and circumesophageal muscle cells) are derived from secondary mesenchyme cells (SMC) in sea urchin embryos. To gain information on the specification and differentiation processes of SMC-derived cells, we studied the exact number and division cycles of each type of cell in Hemicentrotus pulcherrimus. Numbers of blastocoelar cells, coelomic pouch cells and circumesophageal muscle fibers were 18.0 +/- 2.0 (36 h post-fertilization (h.p.f.)), 23.0 +/- 2.5 (36 h.p.f.) and 9.5 +/- 1.3 (60 h.p.f.), respectively, whereas the number of pigment cells ranged from 40 to 60. From the diameters of blastocoelar cells and coelomic pouch cells, the numbers of division cycles were elucidated; these two types of cells had undertaken 11 rounds of cell division by the prism stage, somewhat earlier than pigment cells. To determine the relationship among the four types of cells, we tried to alter the number of pigment cells with chemical treatment and found that CH3COONa increased pigment cells without affecting embryo morphology. Interestingly, the number of blastocoelar cells became smaller in CH3COONa-treated embryos. In contrast, blastocoelar cells were markedly increased with NiCl2 treatment, whereas the number of pigment cells was markedly decreased. The number of coelomic pouch cells and circumesophageal muscle fibers was not affected with these treatments, indicating that coelomic pouch and muscle cells are specified independently of, or at much later stages, than pigment and blastocoelar cells.

Cloning and functional analysis of ascidian Mitf in vivo: insights into the origin of vertebrate pigment cells

Reflecting on the iridophore transcriptome, and more

Urochordate βγ-Crystallin and the Evolutionary Origin of the Vertebrate Eye Lens

Dna, Rna, and Protein Synthesis of Pigment Cells in Culture

Melanin targeting for intracellular drug delivery: Quantification of bound and free drug in retinal pigment epithelial cells

Disposition of ophthalmic timolol in treated and untreated rabbit eyes. A multiple and single dose study

Many readers of PCMR recently traveled to their respective pigment cell research society meetings or will be traveling to the upcoming Society for Melanoma Research meeting. These are always exciting opportunities to present new findings, hear about new results that inspire new experiments, and meet colleagues from around the globe. These meetings serve to educate and inform the research community and enhance the pace of pigment and melanoma cell research. The sharing of information and resources is a crucial part of this process. The best constructs, cell lines, tissue resources, and animal models are difficult to develop, but are of immense value to different investigators studying specific aspects of pigment cell and melanoma research. There are perceived and occasionally real risks of others developing overlapping research programs based on the use of these resources; however, the development and widespread use of these tools with minimal restrictions is critical to move research forward. Such a collaborative research approach has become much more common in recent years – indeed, it is often vital, for many of the complex biological problems currently being evaluated require a diversity of skill-sets rarely seen in anything but the largest labs. Despite the inherent difficulties in getting multiple investigators to work together, the broader range of expertise has allowed for major advances in pigment cell and melanoma biology over the past several years. An increasingly common topic of conversation at these research meetings is the difficulty in getting and retaining adequate funding for research. At times, this creates an atmosphere in which individual goals of obtaining funding takes precedence over broader goals, sometimes to the detriment of other investigators. Competition is an inherent part of human nature, but nearly every investigator can recall examples of paper or grant reviews that cannot be construed as constructive or fair even by the most objective observer. We are happy to say that the proportion of reviews submitted to PCMR that are unfairly negative is very small. Indeed, the majority are constructive, thoughtful critiques, and some are truly exemplary reviews, with a level of detail that is impressive to behold. As editors, we applaud those who take the time to make such sacrificial efforts on behalf of their colleagues in the field, efforts that allow the authors to make genuine improvements to the presentation and impact of their work. What is to be done about clearly inappropriate reviews? If we receive unsubstantiated, subjective reviews, we either seek additional input or may simply ignore reviews that are negative without significant substance. The pigment cell community is a relatively small one, so that a co-operative and considerate approach in the long run will always pay dividends; the entire research community suffers when merit-based evaluation of papers does not occur.

It has been over 8 years since the journal Pigment Cell Research incorporated melanoma into its name and broadened its catchment of research submissions. During that time, the melanoma field has made broad strides including the characterization of different genomic subsets of melanomas, understanding the role of the microenvironment in tumor progression, and demonstrating efficacy of targeted inhibitors and immune checkpoint blockade agents in advanced-stage melanoma patients. Indeed, one would be hard pushed to find a tumor type in which the advances have been so remarkable during this time period. The current treatment landscape for advanced-stage melanoma patients now offers a high chance for a durable response, a situation that few imagined possible at the start of 2008. While it is appropriate to laud these advances, the field must not rest on its laurels. The white paper, ‘The State of Melanoma: challenges and opportunities’, in this issue of PCMR is directed at continuing to push fronts in the melanoma field. As this field continues to explore high impact translational questions, one must not forget melanomas ‘dendritic’ roots in the pigment cell research field. Many of the current major questions within the melanoma field can be traced to seminal studies in pigment cell biology. One clear example of the influence of pigment cell research is MITF. This transcription factor was first identified as a mutated gene associated with loss of pigmentation but was more recently found to be amplified in melanoma and alterations in its expression linked to drug-resistant melanoma cell populations. Other transcription factors, FOXD3 and PAX3, that were originally studied for their role in the differentiation/dedifferentiation of neural crest cells, have also been associated with drug-tolerant states. It is now clear that many malignant traits in melanomas are modulated by melanocytic-lineage selective factors. In considering some of the critical questions posed in the white paper, it will be important to take into account the findings from the pigment cell developmental and disorders fields. Understanding mechanisms underlying cellular dormancy of melanoma cells, exploring factors that direct melanomas to metastasize to the brain and identifying determinants of response and resistance to immune checkpoint agents will be enriched by considering knowledge gained from studies in normal pigmented cells. Furthermore, models that have been used for years to visualize altered pigmentation of the skin and other tissues are now being modified/extended to measure melanoma growth in the context of therapeutic intervention and to visualize the dissemination of melanocytic cells even at the single-cell level. While PCMR offers one avenue to promote discussion across fields, we should take advantage of other opportunities. Cross attendance at international meetings of societies associated with the journal is a venue to exchange views. In the next 6 months, we look forward to meetings of the European Society for Pigment Cell Research (Milan, September), PanAmerican Society for Pigment Cell Research (Baltimore, October), and Society for Melanoma Research (Boston, November). At the funding level, there is a growing emphasis on team science collaborative awards from foundations as well as federal sources. Such efforts benefit from being cross-disciplinary, new initiatives involving multiple institutions. All these efforts should promote the bidirectional sharing of ideas, resources, and collaborations, and help investigators to continue to meet the challenges and opportunities that arise in the melanoma and pigment cell research fields.