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. 1997 Aug;146(4):1407–1415. doi: 10.1093/genetics/146.4.1407

Genetic Studies of the Mouse Mutations Mahogany and Mahoganoid

K A Miller 1, T M Gunn 1, M M Carrasquillo 1, M L Lamoreux 1, D B Galbraith 1, G S Barsh 1
PMCID: PMC1208084  PMID: 9258683

Abstract

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 α-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 α-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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Selected References

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  1. Huszar D., Lynch C. A., Fairchild-Huntress V., Dunmore J. H., Fang Q., Berkemeier L. R., Gu W., Kesterson R. A., Boston B. A., Cone R. D. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997 Jan 10;88(1):131–141. doi: 10.1016/s0092-8674(00)81865-6. [DOI] [PubMed] [Google Scholar]
  2. Jackson I. J. Molecular and developmental genetics of mouse coat color. Annu Rev Genet. 1994;28:189–217. doi: 10.1146/annurev.ge.28.120194.001201. [DOI] [PubMed] [Google Scholar]
  3. Jones B. H., Kim J. H., Zemel M. B., Woychik R. P., Michaud E. J., Wilkison W. O., Moustaid N. Upregulation of adipocyte metabolism by agouti protein: possible paracrine actions in yellow mouse obesity. Am J Physiol. 1996 Jan;270(1 Pt 1):E192–E196. doi: 10.1152/ajpendo.1996.270.1.E192. [DOI] [PubMed] [Google Scholar]
  4. Kapur R. P., Yost C., Palmiter R. D. Aggregation chimeras demonstrate that the primary defect responsible for aganglionic megacolon in lethal spotted mice is not neuroblast autonomous. Development. 1993 Mar;117(3):993–999. doi: 10.1242/dev.117.3.993. [DOI] [PubMed] [Google Scholar]
  5. Lamoreux M. L., Galbraith D. B. DK/Lm: a strain of laboratory mouse with an unusual expression of the lethal yellow (Ay) phenotype. Genet Res. 1986 Aug;48(1):35–40. doi: 10.1017/s0016672300024630. [DOI] [PubMed] [Google Scholar]
  6. Lu D., Willard D., Patel I. R., Kadwell S., Overton L., Kost T., Luther M., Chen W., Woychik R. P., Wilkison W. O. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature. 1994 Oct 27;371(6500):799–802. doi: 10.1038/371799a0. [DOI] [PubMed] [Google Scholar]
  7. McCulloch E. A., Siminovitch L., Till J. E., Russell E. S., Bernstein S. E. The cellular basis of the genetically determined hemopoietic defect in anemic mice of genotype Sl-Sld. Blood. 1965 Oct;26(4):399–410. [PubMed] [Google Scholar]
  8. Michaud E. J., Bultman S. J., Klebig M. L., van Vugt M. J., Stubbs L. J., Russell L. B., Woychik R. P. A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (Ay) mutation. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2562–2566. doi: 10.1073/pnas.91.7.2562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Millar S. E., Miller M. W., Stevens M. E., Barsh G. S. Expression and transgenic studies of the mouse agouti gene provide insight into the mechanisms by which mammalian coat color patterns are generated. Development. 1995 Oct;121(10):3223–3232. doi: 10.1242/dev.121.10.3223. [DOI] [PubMed] [Google Scholar]
  10. Mountjoy K. G., Robbins L. S., Mortrud M. T., Cone R. D. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992 Aug 28;257(5074):1248–1251. doi: 10.1126/science.1325670. [DOI] [PubMed] [Google Scholar]
  11. Poole T. W. Dermal-epidermal interactions and the action of alleles at the agouti locus in the mouse. Dev Biol. 1975 Feb;42(2):203–210. doi: 10.1016/0012-1606(75)90329-2. [DOI] [PubMed] [Google Scholar]
  12. Robbins L. S., Nadeau J. H., Johnson K. R., Kelly M. A., Roselli-Rehfuss L., Baack E., Mountjoy K. G., Cone R. D. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell. 1993 Mar 26;72(6):827–834. doi: 10.1016/0092-8674(93)90572-8. [DOI] [PubMed] [Google Scholar]
  13. Shimizu H., Shargill N. S., Bray G. A., Yen T. T., Gesellchen P. D. Effects of MSH on food intake, body weight and coat color of the yellow obese mouse. Life Sci. 1989;45(6):543–552. doi: 10.1016/0024-3205(89)90105-7. [DOI] [PubMed] [Google Scholar]
  14. Siracusa L. D. The agouti gene: turned on to yellow. Trends Genet. 1994 Dec;10(12):423–428. doi: 10.1016/0168-9525(94)90112-0. [DOI] [PubMed] [Google Scholar]
  15. Vrieling H., Duhl D. M., Millar S. E., Miller K. A., Barsh G. S. Differences in dorsal and ventral pigmentation result from regional expression of the mouse agouti gene. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5667–5671. doi: 10.1073/pnas.91.12.5667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Willard D. H., Bodnar W., Harris C., Kiefer L., Nichols J. S., Blanchard S., Hoffman C., Moyer M., Burkhart W., Weiel J. Agouti structure and function: characterization of a potent alpha-melanocyte stimulating hormone receptor antagonist. Biochemistry. 1995 Sep 26;34(38):12341–12346. doi: 10.1021/bi00038a030. [DOI] [PubMed] [Google Scholar]
  17. Wilson B. D., Ollmann M. M., Kang L., Stoffel M., Bell G. I., Barsh G. S. Structure and function of ASP, the human homolog of the mouse agouti gene. Hum Mol Genet. 1995 Feb;4(2):223–230. doi: 10.1093/hmg/4.2.223. [DOI] [PubMed] [Google Scholar]
  18. Wintzen M., Gilchrest B. A. Proopiomelanocortin, its derived peptides, and the skin. J Invest Dermatol. 1996 Jan;106(1):3–10. doi: 10.1111/1523-1747.ep12326950. [DOI] [PubMed] [Google Scholar]
  19. Yang Y. K., Ollmann M. M., Wilson B. D., Dickinson C., Yamada T., Barsh G. S., Gantz I. Effects of recombinant agouti-signaling protein on melanocortin action. Mol Endocrinol. 1997 Mar;11(3):274–280. doi: 10.1210/mend.11.3.9898. [DOI] [PubMed] [Google Scholar]
  20. Yen T. T., Gill A. M., Frigeri L. G., Barsh G. S., Wolff G. L. Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene. FASEB J. 1994 May;8(8):479–488. doi: 10.1096/fasebj.8.8.8181666. [DOI] [PubMed] [Google Scholar]
  21. Zemel M. B., Kim J. H., Woychik R. P., Michaud E. J., Kadwell S. H., Patel I. R., Wilkison W. O. Agouti regulation of intracellular calcium: role in the insulin resistance of viable yellow mice. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4733–4737. doi: 10.1073/pnas.92.11.4733. [DOI] [PMC free article] [PubMed] [Google Scholar]

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