Genetics, Vol 146, 1407-1415, Copyright © 1997

INVESTIGATIONS

Genetic Studies of the Mouse Mutations mahogany and mahoganoid

K. A. Miller, T. M. Gunn, M. M. Carrasquillo, M. L. Lamoreux, D. B. Galbraith and G. S. Barsh
Departments of Pediatrics and Genetics, and the Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, 94305-5428

The mouse mutations mahogany (mg) and mahoganoid (md) are negative modifiers of the Agouti coat color gene, which encodes a paracrine signaling 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 protein is normally expressed in the skin and acts as an antagonist of the melanocyte receptor for {alpha}-MSH (Mc1r); however, ectopic expression of Agouti causes obesity, possibly by antagonizing melanocortin receptors expressed in the brain. To investigate where md and mg lie in a genetic pathway with regard to Agouti and Mc1r signaling, we determined the effects of these mutations in animals that carried either a loss-of-function Mc1r mutation (recessive yellow, Mc1r(e)) or a gain-of-function Agouti mutation (lethal yellow, A(y)). We found that the Mc1r(e) mutation suppressed the effects of md and mg, but that md and mg suppressed the effects of A(y) on both coat color and obesity. Plasma levels of {alpha}-MSH and of ACTH were unaffected by md or mg. These results suggest that md and mg interfere directly with Agouti signaling, possibly at the level of protein production or receptor regulation.

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