Molecular Genetics and
Development of Melanocytes

 

Summary

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...

 

 

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. We have shown that red or yellow dogs have a truncated MC1R Newton et al 2000).

 

In collaboration with Jonathan Rees (University of Edinburgh) we demonstrated some years ago that most occurences of red hair in humans was due to two copies of a variant MC1R gene. We have recently used transgenic mice to show that the normal human MC1R will "rescue" the recessive yellow mouse phenotype. The transgenic mouse assay shows that red-hair associated variants of human MC1R have reduced activity, but still have some residual function (Healy et al 2001). We are continuing the transgenic mouse studies to understand the signalling mechanisms that causes the switch in melanin type. We are also looking at the MC1R gene in other species, in particular zebrafish, that may provide an additional genetic and cell biological model for MC1R function (Logan et al 2003).

Left, recessive yellow mouse. Right, recessive yellow mouse containing human MC1R transgene

 

Dr Ian Jackson's Key Publications

Collaborations

• Professor Jonathan Rees Systems Dermatology, University of Edinburgh
• Professor Sue Fleetwood-Walker University of Edinburgh
  

 

Lab Members

Current lab members involved in this work are:

• Dr Pleasantine Mill
• Peter Budd
• Margaret Keighren
• Dr Sally Cross
• Dr Richard Mort

 

1. Molecular Genetics and Development of Melanocytes (this page)
   
2. Genetic Models of Human Disease

 

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 many 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.

 

Purpose

There are many mutations that affect the developmental and cell biology of melanoctytes. 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 hair follicles, and KIT is a candidate for controlling this migration. We recently have shown, using an in vitro skin culture system, that KIT does not seem to direct the migration of melanoblasts into hair follicles, but activation of the receptor does accelerate their movement. (Jordan and Jackson 2000). In collaboration with others these mice have enabled the identification of melanocyte stem cells in the hair follicle (Nishimura et al 2002) and the demonstration that Bcl2 is a target for the transcription factor MITF (McGill et al 2002). Using chimaeric embryos and mosiac transgenic mice we have reinvestigated the melanoblast lineage (Wilkie et al 2002) and the development of the telencephalon (Wilkie et al 2004).

 

More recently we have used the transgenic line as a reporter of embryonic development to identify novel ENU- mutations affecting embryogenesis. A combination of mouse mutants, transgenic mice and culture systems offers a powerful means of understanding melanocyte development, and gaining insight into fundamental principles of developmental biology.

 

 

A 10.5 day embryo carrying the Dct-LacZ trangene, stained with Xgal to reveal blue-stained migrating melanoblasts.