Ian Jackson: Molecular Genetics and Development of Melanocytes
Molecular Genetics and Development of Melanocytes
Melanocytes, the cells which produce melanin pigment in skin and hair, are an excellent system for understanding fundamental principles of developmental and cell biology. These cells arise in the neural crest and begin to migrate as melanoblasts through the developing dermis. They subsequently cross to the epidermis and ultimately become localised on the dermal-epidermal junction in the skin or within hair follicles. Once at their final site they begin to synthesis melanin and transfer it as granules to neighbouring keratinocytes...
In collaboration with Jonathan Rees (University of Edinburgh) we demonstrated some years ago that most occurrences of red hair in humans were due to two copies of a variant MC1R gene. We have used transgenic mice to show that the normal human MC1R will "rescue" the recessive yellow mouse phenotype, but the pharmacology of the human receptor is different from the mouse. In a transgenic mouse assay we have shown that red-hair associated variants of human MC1R have reduced activity, but some still have residual function that allows the switch in melanin type. We are also looking at the MC1R gene in other species, in particular zebrafish, which may provide an additional genetic and cell biological model for MC1R function.
Mouse coat colour genetics has been studied for over 100 years, and provides a rich source of mutations that affect many aspects of melanocyte development and function. The genes underlying most of these mutations have now been identified. Those mutations that affect early development are often in genes that encode cell surface receptors, their ligands, or transcription factors. Mutations that affect later function of melanocytes are found in a range of genes, including those for receptors and ligands, but also encoding enzymes, structural proteins and proteins involved in organelle biosynthesis.
There are many mutations that affect the developmental and cell biology of melanocytes. These mutations then give access to the genes underlying these processes. By studying these genes and mutations we can answer fundamental questions of biology in a tractable model system.
Approach, Progress and Future Work
We use transgenic and mutant mice to study the genetic control of the development of melanocytes, and their progenitors; neural crest cells and melanoblasts. We have produced a particularly valuable transgenic line in which LacZ is expressed in developing melanoblasts . Using these mice, we showed some years ago that the receptor tyrosine kinase, KIT, which was originally identified as a coat colour mutation, is necessary for survival of melanoblasts during development. Melanoblasts are somehow guided in their migration to populate the developing skin and hair follicles, and KIT is a candidate for controlling this migration. Recently we have developed an ex vivo, live imaging system to visualise fluorescently labelled migrating melanoblasts, in which we can assay the migratory and proliferation properties of these cells.
We have also developed additional transgenic mouse reporter lines, including Fucci2a, which provides cell-specific cell cycle information in live cells, tissue or embryos. We are also developing cell-culture based methods for examining melanoblast, melanocyte and melanoma behaviour with the goal of replacing the use of animals for such work.
Melanocytes make two types of melanin; eumelanin, which is black or brown, and phaeomelanin, which is red or yellow. Signalling through a G-protein coupled receptor, MC1R, stimulates melanocytes to synthesise eumelanin. In absence of signalling, melanocytes make phaeomelanin. Mutations or variants in MC1R in many species affect the balance between phaeomelanin and eumelanin. Recessive yellow mice, for example, have a frameshift in the gene encoding MC1R and we showed that red and yellow dogs have a truncated MC1R protein.