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A biochemical function for attractin in agouti-induced pigmentation and obesity

Nature Genetics volume 27, pages 40–47 (2001)Cite this article

Abstract

Agouti protein, a paracrine signaling molecule normally limited to skin, is ectopically expressed in lethal yellow (Ay) mice, and causes obesity by mimicking agouti-related protein (Agrp), found primarily in the hypothalamus. Mouse attractin (Atrn) is a widely expressed transmembrane protein whose loss of function in mahogany (Atrnmg-3J/ Atrnmg-3J) mutant mice blocks the pleiotropic effects of Ay. Here we demonstrate in transgenic, biochemical and genetic-interaction experiments that attractin is a low-affinity receptor for agouti protein, but not Agrp, in vitro and in vivo. Additional histopathologic abnormalities in Atrnmg-3J/Atrnmg-3J mice and cross-species genomic comparisons indicate that Atrn has multiple functions distinct from both a physiologic and an evolutionary perspective.

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Figure 1: Expression of Atrn mRNA as determined by in situ or northern-blot hybridization.
Figure 2: Spongy degeneration in Atrnmg-3J/Atrnmg-3J mice.
Figure 3: Effect of Atrn transgenes on coat color.
Figure 4: Biochemical interaction of ATRNEc with agouti protein or Agrp.
Figure 5: Interaction of Atrnmg-3J with A or Agrp in vivo.
Figure 6: Evolutionary conservation of Atrn.
Figure 7: Atrn is an accessory receptor for agouti protein.

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Acknowledgements

We thank P. Kim and R. Saxena for technical assistance; C. Hwu, M. Ollmann, K. Willert, B. Wilson and J. Xu for advice about experimental design and data presentation; Y. Chen for construction of transgenic mice; P. Budd and I. Jackson for the Dct promoter construct; and H. Lee for assistance with animal breeding and genotyping. This work was supported by grants to G.S.B. (DK-48506) and to S.J.W. (MH42251) from the National Institutes of Health, and by a American Heart Association Western States fellowship award to T.M.G. G.S.B. is an Associate Investigator of the Howard Hughes Medical Institute. L.H. carried out the protein interaction studies and T.M.G. carried out the genetic interaction experiments.

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Author notes

  1. Lin He and Teresa M. Gunn: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Pediatrics and Genetics and the Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA

    Lin He, Teresa M. Gunn & Gregory S. Barsh

  2. Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California, USA

    Donna M. Bouley

  3. Mental Health Research Institute, University of Michigan School of Medicine, Ann Arbor, Michigan, USA

    Xin-Yun Lu & Stanley J. Watson

  4. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts , USA

    Stuart F. Schlossman & Jonathan S. Duke-Cohan

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Correspondence to Gregory S. Barsh.

Supplementary information

Web Figure A

Alignment of the complete amino acid alignment of the predicted Atrn proteins encoded by the mouse and Drosophila cDNAs, and by the C. elegans genome sequence. Identities and similarities are shaded in black and gray, respectively, and conserved domains indicated by colored bars. (GIF 83 kb)

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He, L., Gunn, T., Bouley, D. et al. A biochemical function for attractin in agouti-induced pigmentation and obesity. Nat Genet 27, 40–47 (2001). https://doi.org/10.1038/83741

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