Molecular genetics and development of melanocytes

The cells that produce the pigment in hair and skin, melanocytes, develop from cells in the embryo that also produce cells of the nervous system. Understanding how these very different cell types come from a single precursor is an important question in developmental biology. As this is a fairly simple developmental process and one that can be studied in culture, rather than in live embryos, it acts as a model for the understanding of more complex events. We are investigating what molecules direct this process, by blocking the action of specific genes and by examining mouse embryos in which genes have been mutated.

The amount and type of pigment that melanocytes make is controlled by a protein on the cell surface. Individuals in whom this protein is less active usually have red hair and skin that burns easily in the sun. We are studying human populations to identify other molecules that interact in this process to affect sun sensitivity. We are also looking at other functions for this protein; it has been suggested that it is involved in feeling pain and the effectiveness of pain killers or anaesthetics.

Melanocytes differentiate and migrate from the neural crest during mammalian development. We are able to culture neural tubes from early mouse embryos and skin from later embryos and melanoblasts proliferate and migrate within the cultures. We have developed a live-imaging system which allows us to observe migrating cells within the skin and their localisation to the hair follicles. We can manipulate the system with drugs which inhibit receptors, kinases etc investigate the pathways controlling the migration, or can use cultures derived from mutant mice to see the effect of loss of other genes.

The MSH receptor, MC1R, controls the type of melanin made by the melanocyte. Variants in the protein are common in the Caucasian population and two variant alleles usually results in red hair and pale skin. Other genes modify the effect of MC1R variants and we are undertaking a study to assess what role is played by variation in candidate modifiers. Mouse and human MC1R are different in the strength of their signalling, and their dependence on ligand binding. We have analysed mice in which we have replaced the mouse receptor with the human one and demonstrated differences in signalling between the two. We are interested in the mechanism by which agouti signalling protein, ASP, modulates signalling at MC1R.

We have identified two novel mouse mutations that affect the signalling through MC1R and have identified the genes affected in both cases. These are providing insight into the mechanism of signalling downstream of MC1R, and the regulation of the ASP/MC1R interaction.

MC1R has been suggested to be involved in pain response and analgesia and in inflammatory responses. We have investigated this role using transgenic and mutant mice. We find that female mice mutant for MC1R have a reduced sensitivity to noxious heat, but an enhanced sensitivity to noxious cold. Males however are unaffected. The hyperalgesic and allodynic effects of inflammation are also enhanced in the mutants.