The melanocortin signaling pathway

The spectrum of color and diversity of patterns that we see in mammals arises from variation in the quantity, quality, and regional distribution of two types of pigment—black eumelanin and yellow pheomelanin. Switching between eumelanin and pheomelanin production—a process commonly known as pigment “type-switching”— is controlled primarily by the melanocortin system, in which a family of G protein–coupled receptors has been implicated not only in pigmentation but also in cortisol production, body weight regulation, and exocrine gland secretion.

Our current understanding of melanocortin biology stems from the identification in laboratory mice of Mc1r mutations as the cause of recessive yellow and Agouti mutations as the cause of lethal yellow. Pigment type-switching is controlled primarily by the Melanocortin 1 receptor (Mc1r) and Agouti, which encode a seven transmembrane–domain receptor and its extracellular ligand, respectively. We are interested in using this system to understand the process whereby a hormone-receptor interaction triggers a cell biological switch.

Pigment-type switching provides a tractable genetic model for identifying additional components of the melanocortin system through genetic mapping of coat color traits in mammalian species. Positional cloning of mouse coat color mutations has revealed that two accessory proteins, Attractin and Mahogunin, are required for Agouti signaling. Also, mapping of the genetic basis for black coat color in domestic dogs has recently led to the discovery of a previously unrecognized melanocortin receptor ligand, β-defensin 103 (CBD103). Studies with other β-defensins and additional melanocortin receptors reveal the potential for extensive cross-talk between the ligands and melanocortin system. We are currently using molecular genetic, biochemical, and cell-based approaches to study the role of these components in melanocortin signaling.