GENETIC-STUDIES OF THE MOUSE MUTATIONS MAHOGANY AND MAHOGANOID

The mouse mutations mahogany (mg) and mahoganoid (md) are negative mod ifiers of the Agouti coat color gene, which encodes a paracrine signal ing molecule that induces a switch in melanin synthesis from eumelanin to pheomelanin. Animals mutant for md or mg synthesize very little or no pheomelanin depending on Agouti gene background. The Agouti protei n is normally expressed in the skin and acts as an antagonist of the m elanocyte receptor for alpha-MSH (Mc1r); however, ectopic expression o f Agouti causes obesity, possibly by antagonizing melanocortin recepto rs expressed in the brain. To investigate where md and mg lie in a gen etic pathway with regard to Agouti and Mc1r signaling, we determined t he effects of these mutations in animals that carried either a loss-of -function Mc1r(e) mutation (recessive yellow, Mc1r(e)) or a gain-of-fu nction Agouti mutation (lethal yellow, A(y)). We found that the Mc1r(1 ) mutation suppressed the effects of md and mg, but that md and mg sup pressed the effects of A(y) On both coat color and obesity. Plasma lev els of alpha-MSH and of ACTH were unaffected by md or mg. These result s suggest that md and mg interfere directly with Agouti signaling, pos sibly at the level of protein production or receptor regulation.