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Biology of Mammalian Pigmentation
Summary: Greg Barsh is interested in understanding the genetic and biochemical mechanisms responsible for mammalian color variation.
Our laboratory studies basic aspects of cell and organismal biology, as applied to mammalian development and disease. Most of our projects are based on the genetics of pigmentation, a model system that is experimentally tractable and relevant to human health.
Pigment Type-Switching
Agouti protein is a paracrine signaling molecule produced by specialized cells in the skin that causes melanocytes in the overlying hair follicle to switch from the synthesis of one pigment type, black/brown eumelanin, to an alternative form, red/yellow pheomelanin. Over the past several years, work from our laboratory and others demonstrated that Agouti protein promotes yellow pigment synthesis by binding to and signaling via a G protein–coupled receptor expressed on melanocytes known as the melanocortin 1 receptor (Mc1r).
Besides Agouti and Mc1r, mutations in at least 10 additional genes can interfere with the switching of pigment type. We recently determined that one member of this class encodes Attractin (Atrn), a large single-transmembrane protein that is expressed widely throughout the body but functions in melanocytes as an accessory receptor for Agouti protein. Expression of both Atrn and Mc1r on melanocytes is an absolute requirement for Agouti protein signaling; however, Mc1r lies genetically downstream of Atrn. Furthermore, in the absence of Agouti, mutations of Mc1r but not of Atrn can affect pigmentation. Thus, the intracellular effects of Agouti protein signaling are mediated via Mc1r, while cell surface interaction with Atrn permits signaling to take place. Our current effort is directed at understanding the biochemical basis for these observations and is likely to have wider implications for understanding how peptide hormones signal through G protein–coupled receptors.
Energy Homeostasis
An intriguing aspect of Agouti protein signaling is its ability to cause obesity and increased growth when expressed outside the skin. First recognized more than 100 years ago by gain-of-function mutations that cause obesity and a completely yellow coat, this phenomenon reflects the ability of Agouti protein to mimic a neuropeptide that we named Agouti-related protein (Agrp). Agrp is normally expressed in the hypothalamus, and signals via Mc3r and Mc4r to promote increased feeding and to reduce energy expenditure. Many aspects of the Agrp-Mc4r pathway are homologous or identical to the Agouti protein–Mc1r pathway. Furthermore, both pathways play important roles in human physiology, since loss-of-function mutations in Mc1r cause carrot red hair, fair skin, and freckling, whereas ~5 percent of humans with morbid obesity have loss-of-function mutations in Mc4r. Analysis of genetic variants in both hormones and receptors is helping us understand the structural determinants of receptor affinity and selectivity and also is providing a rational basis for efforts to develop small-molecule Mc3r and Mc4r ligands as pharmaceutical treatments for obesity.
Hypothalamic neurons that express Agrp are located in the arcuate nucleus, where peripheral signals of energy balance are received, integrated, and then engage a series of homeostatic response mechanisms. For example, the circulating hormone leptin, an indicator of body fat stores, has receptors on hypothalamic Agrp neurons and suppresses production of Agrp. Thus, reduced levels of leptin that occur during food deprivation cause increased production of Agrp, thereby stimulating food intake. Current efforts are directed at understanding the circuitry within the hypothalamus through which Agrp and related neuropeptides act, and how different types of peripheral signals are integrated into these circuits.
Pigmentation Patterns
Among the most interesting group of coat color mutations are those whose effects are limited to specific regions of the body, causing stripes, spots, or blocks of pigment in a regular pattern or configuration. A characteristic phenotype in carnivores and ungulates, tabby striping, is unfortunately not found in rodents, but is likely to operate on the Agouti protein–Mc1r pathway described above, since the components of tabby striping are pheomelanin alternating with eumelanin. Spatial control of pheomelanin deposition in mice, however, depends on genetic mechanisms that operate on transcriptional control of Agouti.
The prototypic pale ventral coloration found in many different mammals is caused by a specific Agouti isoform whose expression is restricted to ventral skin. Mechanisms that regulate this isoform act via precise developmental compartments, as manifested by the distinct boundary between dorsal and ventral coloration found in black-and-tan mice, or by the regular regions of red pigment deposition found in certain dog breeds such as the Doberman pinscher. To understand these mechanisms better, we are identifying the underlying DNA regulatory elements that act in cis, and studying unlinked mutations that act in trans to alter ventral-specific Agouti expression.
The Dark Side of Mouse Genetics
A recent area of interest in our lab is a class of pigmentation phenotypes that affect skin rather than hair color. Humans exhibit a tremendous range in both skin and hair color variation, but in mice, color variation is confined mostly to hair. The underlying reason traces back to embryonic development, when pigment cell precursors migrate from the neural crest to the developing skin and then into hair follicles. Interfollicular melanocytes—those that reside between rather than within hair follicles—normally persist in human but not in mouse skin. A better understanding of the mechanisms that underlie this difference could provide general insight into processes of cell death, migration, or differentiation.
In a collaboration with Martin Hrabe de Angelis (Institute of Experimental Genetics, Neuherberg, Germany), we have begun to study a large number of mutations that cause dark skin in mice. Approximately 25 new mutations have been identified to date that can be classified according to the body regions affected, presence in hairy or nonhairy skin, portion of the skin affected, and whether or not there is a concomitant darkening of hair. Candidate genes include a tyrosine kinase receptor, an intermediate filament protein, and a transcription factor, suggesting this approach will survey a broad range of cellular processes.
Last updated July 23, 2003
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