The mouse as a model for human melanocyte and melanoma development
Image: E10.5 DCT-LacZ mouse embryo. β-Gal stain (blue) identifies individual melanoblasts in addition to neural and craniofacial sructures.
Melanocytes are the pigment producing cells within the skin. Melanocytes give rise to melanoma, a particularly invasive and deadly tumor type. In order to better understand genes that are important in melanoma risk and progression, we are interested in the important pathways that regulate development of melanoblasts, or melanocyte stem cells. Historically, many of the pathways that regulate melanocyte development, pigment production and propensity to transform to melanoma were discovered with investigation of mouse pigmentation mutations. We have assembled a number of mouse pigmentation mutations, identified through random insertional mutagenesis screens or mouse chemical mutagenesis screens that are involved in regulating melanocyte numbers within the skin. Investigation of the molecular basis of these mouse pigmentation phenotypes identifies new candidates genes and pathways that may control normal human pigmentation phenotypes. In order to test for the role of these genes in human pigmentation we have isolated DNA from a large collection of Colorado children who are part of a longitudinal study of melanocytic nevus development. Some of these children have been followed since 3 years of age with annual skin exams that have kept track of pigmentation phenotypes such as skin, hair and eye color, and numbers and size of incident and pre-existing melanocytic nevi. The majority of children are now 9 years of age. We are examining genetic polymorphisms in a number of important mouse melanocyte development pathways that may play a role in determining normal human pigmentation phenotypes and in melanoma risk. Our interests also include characterisation of the major gene expression differences between human melanoblasts isolated from foreskin, and differentiated melanocytes. We are comparing these gene expression profiles with those from malignant melanoma in order to investigate putative "melanoma stem cell" markers that may have therapeutic significance.
Selected Peer-Reviewed Publications
- Geng Liu, Tamara Terzian, Shunbin Xiong, Carolyn S. Van Pelt, Arlette Audiffred, Neil F. Box, and Guillermina Lozano (2007) The p53-Mdm2 network in progenitor cell expansion during mouse postnatal development Journal of Pathology, Sept 24; [Epub ahead of print]
- Tamara Terzian, YongXing Wang, Neil F. Box, Carolyn Van Pelt, Guillermina Lozano (2007) Haploinsufficiency of MDM2 and MDM4 in tumorigenesis and development. Molecular and Cellular Biology, 27(15):5479-5485.
- Duffy DL, Box NF, Chen W, Palmer JS, Montgomery G, Green AC, Martin NG, and Sturm RA (2004) Interactive effects of MC1R and OCA2 on melanoma risk phenotypes. Human Molecular Genetics 13(4):447-461.
- Kile, BT, Hentges K, Clark AT, Salinger AP, Box NF, Johnson RL, Behringer R, Bradley A, Justice MJ (2003) Functional genetic analysis of mouse Chromosome 11 by the large-scale isolation of recessive mutations using a balancer chromosome. Nature 425(6935):81-86.
- Sturm RA, Duffy DL, Box NF, Chen W, Smit DJ, Brown DL, Stow JL, Leonard HJ and Martin NG (2003) The role of melanocortin-1 receptor polymorphism in skin cancer risk phenotypes. Pigment Cell Research 16:266-272.
- Sturm RA, Duffy DL, Box NF, Newton RA, Shepherd AG, Chen W, Marks LH, Leonard HJ and Martin NG (2003) Genetic association and cellular function of MC1R variant alleles in human pigmentation. Annals of the New York Academy of Science 994: 348-358.
- AG Smith*, NF Box*, LH Marks, W Chen, DJ Smit, JR Wyeth, GA Huttley, S Easteal and RA Sturm (2001) The human melanocortin-1 receptor locus: analysis of transcription unit, locus polymorphism and haplotype evolution. Gene 281:81-94.
*Equal contributions were made towards this work by the first 2 authors.
- Box NF and Sturm RA (2001) Skin colour and skin cancer - the genetic link, Todays Life Sciences 15: 79-84.
- Sturm RA, Teasdale RD, Box NF, (2001) Human pigmentation genes: identification, structure and consequences of polymorphic variation. Gene 281(1-2):81-94.
- Voisey J, Box NF, van Daal A (2001) A Polymorphism Study of the Human Agouti Gene and Its Association with MC1R. Pigment Cell Research 14:264-267.
- Box NF, Duffy DL, Chen W, Stark M, Martin NG, Sturm RA, Hayward NK (2001) MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations. American Journal of Human Genetics 69: 765-773.
- Box NF, Duffy DL, Irving RE, Russell A, Chen W, Griffyths LR, Parsons PG, Green AC, Sturm RA (2001) Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma. Journal of Investigative Dermatology 116(2):224-229.
- Palmer JS*, Duffy DL*, Box NF*, Aitken JF, O'Gorman LE, Green AC, Hayward NK, Martin NG, Sturm RA (2000) Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? American Journal of Human Genetics 66(1):176-86.
*Equal contributions were made towards this work by the first 3 authors.
- Richard A. Sturm, Neil F. Box, and Michele Ramsay. (1998) Human pigmentation genetics: the difference is only skin deep. Bioessays, 20(9): 712-721.
- N.F. Box, J.R. Wyeth, L.E. O?Gorman, N.G. Martin and R.A. Sturm. (1997) Characterisation of melanocyte-stimulating hormone receptor variant alleles in twins with red hair. Human Molecular Genetics, 6(11): 1891-1897.