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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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.
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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