Mechanisms for the pleiotropic effects of the agouti gene

The agouti locus is one of several classic genetic loci that affect the coat color of mice. The wild-type agouti phenotype, exemplified by dorsal coat hairs that are black with a single subapical band of yellow and lighter-colored ventral hairs, is found in many mammals including animals of the genera Mus (mice), Oryctolagus (rabbits), Sciurus (squirrels), and Canis (wolves) (reviewed in ref. 1). Much interest has focused on the agouti gene because several dominant mutations result in mice that exhibit adult onset obesity, hyperinsulinemia, and' noninsulindependent diabetes. In addition, mice carrying dominant agouti mutations show an increased susceptibility to a variety of spontaneous and/or induced solid tumors. These mutations provide potential animal models of human disease, and the mouse provides an organism amenable to molecular genetic, biochemical, physiological, and pharmacological manipulations to investigate the causes and treatments of these diseases. The mechanism of action of the agouti gene in all of these phenotypes is under intense investigation. Several recent papers including two in this issue by Klebig et al (2) and Zemel et al (3) now shed light on some modes of action of the agouti protein as well as provide models for in vivo and in vitro tests of agouti function.