International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

I2. Genetic and Biochemical Studies of the Mouse Mahogany/Attractin Gene

T.M. Gunn1, L. He1, J. Duke-Cohan2, G.S. Barsh1.
1Departments of Pediatrics and Genetics, and the Howard Hughes Medical Institute, Stanford University.
Division of Tumor Immunology, Dana-Farber Cancer Institute, Harvard Medical School.

The mouse mahogany (mg) was originally described in the late 1950's as a modifier of the Agouti coat color phenotype; mg mutants make little or no yellow pigment. We recently identified the mg gene, which encodes a widely expressed transmembrane protein orthologous to human Attractin (Atrn). Expression of Atrn in mouse skin is not limited to melanocytes, but using transgenic expression of the Atrn cDNA under control of ubiquitous (b-actin), melanocyte-specific (Dct) and keratinocyte (K14) promoters, we have found that the coat color of mg3-J (amorphic) mutant animals is only rescued in animals with melanocyte expression (b-actin and Dct). This result confirms the identity of the mg gene as Atrn and demonstrates that its effect on pigmentation is melanocyte-autonomous.

Genetic epistasis experiments have revealed an additional role for Atrn in regulation of body weight: mg mutations suppress obesity in Ay mutant animals, which express Agouti protein ubiquitously. Agouti is an endogenous antagonist of melanocortin signaling in the skin and, in vitro, it can antagonize signaling through other melanocortin receptors including the Mc4r which is expressed in the hypothalamus and is involved in regulating feeding behavior. The endogenous antagonist of Mc4r signaling is the Agouti-related protein (Agrp) and mice over-expressing this gene also become obese. Surprisingly, the mg3-J mutation does not suppress obesity in Agrp transgenic animals. Biochemical experiments demonstrate a low-affinity interaction between Attractin and Agouti, but not Attractin and Agrp, suggesting that, in the skin, Atrn functions as a low-affinity receptor for Agouti. Comparison of mg3-J mutant and non-mutant sibs, however, shows that the mg3-J mutation alone results in decreased weight and body fat, suggesting that Atrn is likely to play a role in body weight regulation independent of the Agrp-Mc4r signaling pathway.

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