Networks and pathways in pigmentation, health, and disease

Abstract

Extensive studies of the biology of the pigment-producing cell (melanocyte) have resulted in a wealth of knowledge regarding the genetics and developmental mechanisms governing skin and hair pigmentation. The ease of identification of altered pigment phenotypes, particularly in mouse coat color mutants, facilitated early use of the pigmentary system in mammalian genetics and development. In addition to the large collection of developmental genetics data, melanocytes are of interest because their malignancy results in melanoma, a highly aggressive and frequently fatal cancer that is increasing in Caucasian populations worldwide. The genetic programs regulating melanocyte development, function, and malignancy are highly complex and only partially understood. Current research in melanocyte development and pigmentation is revealing new genes important in these processes and additional functions for previously known individual components. A detailed understanding of all the components involved in melanocyte development and function, including interactions with neighboring cells and response to environmental stimuli, will be necessary to fully comprehend this complex system. The inherent characteristics of pigmentation biology as well as the resources available to researchers in the pigment cell community make melanocytes an ideal cell type for analysis using systems biology approaches. In this review, the study of melanocyte development and pigmentation is considered as a candidate for systems biology-based analyses.

Keywords: development; genetics; melanocyte; melanoma; pigmentation.

Figure 1

The majority of genes known to affect melanocyte development and function have a known role in only one system or disease. Although a multitude of genes have known functions in individual melanocyte cellular processes, few have been correlated with multiple processes and/or human diseases. Each line between a gene and a cellular process or human disease indicates that this gene has been experimentally demonstrated to have a role in this process or disease. Each line between a gene and disease was validated by the presence of an article relating to both the disease and specific gene, identified by a PubMed search (http://www.ncbi.nlm.nih.gov/sites/entrez?db=PubMed). Loss of cells includes WS, and abnormal function includes albinism, piebaldism, HPS, and CHS. Most functions of the genes in these processes have been discovered on an independent basis, using gene-centric, reductionist research approaches. The absence of multiple roles for many pigmentation genes suggests that a full understanding of all the molecules involved is lacking. In the future, a full understanding of all the roles each of these genes plays will reveal many more functions for each gene, covering this diagram with lines. This figure is not meant to be exhaustive, but to illustrate the current knowledge of gene functions in melanocyte cellular systems.

Figure 2

Navigational maps of the regulation and downstream targets of (A) MITF, (B) PAX3, and (C) SOX10, three key transcription factors that govern melanocyte development. Illustrated are the pathways known to be active in developing neural crest precursors to melanoblasts, melanoblasts themselves, or mature melanocytes of mammalian organisms. The black triangles represent DNA promoters/enhancers, illustrating direct transcription factor binding; the absence of direct binding illustrates indirect regulation. Pathways that appear unique to melanoma, details of post-translational modifications, as well as interactions identified in only non-melanocyte cell types or non-mammalian systems to date are excluded from this diagram.