Abstract
Agouti protein and agouti-related protein are homologous paracrine signalling molecules that normally regulate hair colour and body weight, respectively, by antagonizing signalling through melanocortin receptors1,2,3,4,5,6,7. Expression of Agouti is normally limited to the skin, but rare alleles from which Agouti is expressed ubiquitously, such as lethal yellow, have pleiotropic effects that include a yellow coat, obesity, increased linear growth, and immune defects8,9,10,11. The mahogany (mg) mutation suppresses the effects of lethal yellow on pigmentation and body weight, and results of our previous genetic studies place mg downstream of transcription of Agouti but upstream of melanocortin receptors12. Here we use positional cloning to identify a candidate gene for mahogany, Mgca. The predicted protein encoded by Mgca is a 1,428-amino-acid, single-transmembrane-domain protein that is expressed in many tissues, including pigment cells and the hypothalamus. The extracellular domain of the Mgca protein is the orthologue of human attractin, a circulating molecule produced by activated T cells that has been implicated in immune-cell interactions13,14. These observations provide new insight into the regulation of energy metabolism and indicate a molecular basis for crosstalk between melanocortin-receptor signalling and immune function.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lu, D. S. et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371, 799–802 (1994).
Blanchard, S. G. et al. Agouti antagonism of melanocortin binding and action in the B16F10 murine melanoma cell line. Biochemistry 34, 10406–10411 (1995).
Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J. & Cone, R. D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997).
Ollmann, M. M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138 (1997).
Yang, Y.-K. et al. Characterization of agouti-related protein binding to melanocortin receptors. Mol. Endocrinol. 13, 148–155 (1999).
Yang, Y. K. et al. Effects of recombinant agouti-signaling protein on melanocortin action. Mol. Endocrinol. 11, 274–280 (1997).
Shutter, J. R. et al. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev. 11, 593–602 (1997).
Michaud, E. J. et al. Amolecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (Ay) mutation. Proc. Natl Acad. Sci. USA 91, 2562–2566 (1994).
Duhl, D. M. J., Vrieling, H., Miller, K. A., Wolff, G. L. & Barsh, G. S. Neomorphic agouti mutations in obese yellow mice. Nat. Genet. 8, 59–65 (1994).
Roberts, D. W., Wolff, G. L. & Campbell, W. L. Differential effects of the mottled yellow and pseudoagouti phenotypes on immunocompetence in Avy/a mice. Proc. Natl Acad. Sci. USA 81, 2152–2156 (1984).
Gasser, D. L. & Fischgrund, T. Genetic control of the immune response in mice. IV. Relationship between graft vs host reactivity and possession of the high tumor genotypes A y a and A vy a. J. Immunol. 110, 305–308 (1973).
Miller, K. A. et al. Genetic studies of the mouse mutations mahogany and mahoganoid. Genetics 146, 1407–1415 (1997).
Duke-Cohan, J. S. et al. Attractin (DPPT-L), a member of the CUB family of cell adhesion and guidance proteins, is secreted by activated human T lymphocytes and modulates immune cell interactions. Proc. Natl Acad. Sci. USA 95, 11336–11341 (1998).
Duke-Cohan, J. S., Morimoto, C., Rocker, J. A. & Schlossman, S. F. Serum high molecular weight dipeptidyl peptidase IV (CD26) is similar to a novel antigen DPPT-L released from activated T cells. J. Immunol. 156, 1714–1721 (1996).
Jackson, I. J. et al. Genetics and molecular biology of mouse pigmentation. Pigm. Cell Res. 7, 73–80 (1994).
Lane, P. W. & Green, M. C. Mahogany, a recessive color mutation in linkage group V of the mouse. J. Hered. 51, 228–230 (1960).
Nagase, T. et al. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5, 31–39 (1998).
Ramao, M. J. et al. Crystal structure of acidic seminal fluid protein (aSFP) at 1.9 Å resolution: a bovine polypeptide of the spermadhesin family. J. Mol. Biol. 274, 650–660 (1997).
Hishida, R., Ishihara, T., Kondo, K. & Katsura, I. hch-1, a gene required for normal hatching and normal migration of a neuroblast in C. elegans, encodes a protein related to TOLLOID and BMP-1. EMBO J. 15, 4111–4122 (1996).
Bernfield, M. et al. Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans. Annu. Rev. Cell Biol. 8, 365–393 (1992).
Duke-Cohan, J. S., Morimoto, C., Rocker, J. A. & Schlossman, S. F. Anovel form of dipeptidylpeptidase IV found in human serum. Isolation, characterization, and comparison with T lymphocyte membrane dipeptidylpeptidase IV (CD26). J. Biol. Chem. 270, 14107–14114 (1995).
Ollmann, M. M. & Barsh, G. S. Downregulation of melanocortin receptor signaling mediated by the amino-terminus of Agouti protein in Xenopus melanophores. J. Biol. Chem.(submitted).
Ollmann, M. M., Lamoreux, M. L., Wilson, B. D. & Barsh, G. S. Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo. Genes Dev. 12, 316–330 (1998).
Siegrist, W., Stutz, S. & Eberle, A. N. Homologous and heterologous regulation of alpha-melanocyte-stimulating hormone receptors in human and mouse melanoma cell lines. Cancer Res. 54, 2604–2610 (1994).
Dinulescu, D. M. et al. Mahogany (mg) stimulates feeding and increases basal metabolic rate independent of its suppression of agouti. Proc. Natl Acad. Sci. USA 95, 12707–12712 (1998).
Rajora, N. et al. alpha-MSH modulates local and circulating tumor necrosis factor-alpha in experimental brain inflammation. J. Neurosci. 17, 2181–2186 (1997).
Catania, A. et al. The neuropeptide alpha-MSH has specific receptors on neutrophils and reduces chemotaxis in vitro. Peptides 17, 675–679 (1996).
Kakizuka, A. et al. Amouse cdc25 homolog is differentially and developmentally expressed. Genes Dev. 6, 578–590 (1992).
Zuberi, A. R., Nguyen, H. Q., Auman, H. J., Taylor, B. A. & Roopenian, D. C. Agenetic linkage map of mouse chromosome 2 extending from thrombospondin to paired box gene 1, including the h3 minor histocompatibility complex. Genomics 33, 75–84 (1996).
Acknowledgements
We thank J. Westerman for providing mg L/mg L mice; R. Mukherjee for technical assistance; S. Kalman and J. Kerns for help with sequence assembly and agouti protein studies, respectively; A. Zuberi for communicating the results of genetic mapping studies before publication; and H. Sweet for information about the origin of mg 3J. This work was supported by grants to G.S.B., S.F.S. and R.W.D. from the NIH, and by an American Heart Association Western States fellowship award to T.M.G. G.S.B. is an Associate Investigator of the Howard Hughes Medical Institute.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gunn, T., Miller, K., He, L. et al. The mouse mahogany locus encodes a transmembrane form of human attractin. Nature 398, 152–156 (1999). https://doi.org/10.1038/18217
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/18217
This article is cited by
-
Post-developmental extracellular proteoglycan maintenance in attractin-deficient mice
BMC Research Notes (2020)
-
On the origin of serum CD26 and its altered concentration in cancer patients
Cancer Immunology, Immunotherapy (2009)
-
Mouse models for the central melanocortin system
Genes & Nutrition (2009)
-
Attractin gene deficiency contributes to testis vacuolization and sperm dysfunction in male mice
Journal of Huazhong University of Science and Technology [Medical Sciences] (2009)
-
Non-cell autonomous impairment of oligodendrocyte differentiation precedes CNS degeneration in the Zitter rat: Implications of macrophage/microglial activation in the pathogenesis
BMC Neuroscience (2008)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.