Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The mouse mahogany locus encodes a transmembrane form of human attractin

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

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

Figure 1: Expression of Mgca in wild-type and mg mutant mice.
Figure 2: Genetic and physical map of the mg 3J candidate interval.
Figure 3: Predicted protein sequence of Mgca and location of mahogany mutations.
Figure 4: Effect of mg on Agouti protein and potential mechanisms of action of mahogany.

Similar content being viewed by others

References

  1. Lu, D. S. et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371, 799–802 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Blanchard, S. G. et al. Agouti antagonism of melanocortin binding and action in the B16F10 murine melanoma cell line. Biochemistry 34, 10406–10411 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Ollmann, M. M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Yang, Y.-K. et al. Characterization of agouti-related protein binding to melanocortin receptors. Mol. Endocrinol. 13, 148–155 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Yang, Y. K. et al. Effects of recombinant agouti-signaling protein on melanocortin action. Mol. Endocrinol. 11, 274–280 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    CAS  PubMed  Google Scholar 

  12. Miller, K. A. et al. Genetic studies of the mouse mutations mahogany and mahoganoid. Genetics 146, 1407–1415 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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).

    CAS  PubMed  Google Scholar 

  15. Jackson, I. J. et al. Genetics and molecular biology of mouse pigmentation. Pigm. Cell Res. 7, 73–80 (1994).

    Article  CAS  Google Scholar 

  16. Lane, P. W. & Green, M. C. Mahogany, a recessive color mutation in linkage group V of the mouse. J. Hered. 51, 228–230 (1960).

    Article  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    Article  Google Scholar 

  19. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bernfield, M. et al. Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans. Annu. Rev. Cell Biol. 8, 365–393 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. 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).

    Article  CAS  PubMed  Google Scholar 

  22. 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).

  23. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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).

    CAS  PubMed  Google Scholar 

  25. 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).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rajora, N. et al. alpha-MSH modulates local and circulating tumor necrosis factor-alpha in experimental brain inflammation. J. Neurosci. 17, 2181–2186 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Catania, A. et al. The neuropeptide alpha-MSH has specific receptors on neutrophils and reduces chemotaxis in vitro. Peptides 17, 675–679 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Kakizuka, A. et al. Amouse cdc25 homolog is differentially and developmentally expressed. Genes Dev. 6, 578–590 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

Download references

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

Authors

Corresponding author

Correspondence to Gregory S. Barsh.

Rights and permissions

Reprints 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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/18217

This article is cited by

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.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing