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. 2001 Aug;158(4):1683–1695. doi: 10.1093/genetics/158.4.1683

Molecular and phenotypic analysis of Attractin mutant mice.

T M Gunn 1, T Inui 1, K Kitada 1, S Ito 1, K Wakamatsu 1, L He 1, D M Bouley 1, T Serikawa 1, G S Barsh 1
PMCID: PMC1461748  PMID: 11514456

Abstract

Mutations of the mouse Attractin (Atrn; formerly mahogany) gene were originally recognized because they suppress Agouti pigment type switching. More recently, effects independent of Agouti have been recognized: mice homozygous for the Atrn(mg-3J) allele are resistant to diet-induced obesity and also develop abnormal myelination and vacuolation in the central nervous system. To better understand the pathophysiology and relationship of these pleiotropic effects, we further characterized the molecular abnormalities responsible for two additional Atrn alleles, Atrn(mg) and Atrn(mg-L), and examined in parallel the phenotypes of homozygous and compound heterozygous animals. We find that the three alleles have similar effects on pigmentation and neurodegeneration, with a relative severity of Atrn(mg-3J) > Atrn(mg) > Atrn(mg-L), which also corresponds to the effects of the three alleles on levels of normal Atrn mRNA. Animals homozygous for Atrn(mg-3J) or Atrn(mg), but not Atrn(mg-L), show reduced body weight, reduced adiposity, and increased locomotor activity, all in the presence of normal food intake. These results confirm that the mechanism responsible for the neuropathological alteration is a loss--rather than gain--of function, indicate that abnormal body weight in Atrn mutant mice is caused by a central process leading to increased energy expenditure, and demonstrate that pigmentation is more sensitive to levels of Atrn mRNA than are nonpigmentary phenotypes.

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Selected References

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  1. Abelenda M., Puerta M. L. Relationship among food intake, thyroid status and chronic cold-exposure in the rat. Horm Metab Res. 1991 Feb;23(2):90–91. doi: 10.1055/s-2007-1003622. [DOI] [PubMed] [Google Scholar]
  2. Bultman S. J., Klebig M. L., Michaud E. J., Sweet H. O., Davisson M. T., Woychik R. P. Molecular analysis of reverse mutations from nonagouti (a) to black-and-tan (a(t)) and white-bellied agouti (Aw) reveals alternative forms of agouti transcripts. Genes Dev. 1994 Feb 15;8(4):481–490. doi: 10.1101/gad.8.4.481. [DOI] [PubMed] [Google Scholar]
  3. Cheverud J. M., Routman E. J., Duarte F. A., van Swinderen B., Cothran K., Perel C. Quantitative trait loci for murine growth. Genetics. 1996 Apr;142(4):1305–1319. doi: 10.1093/genetics/142.4.1305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Clapham J. C., Arch J. R., Chapman H., Haynes A., Lister C., Moore G. B., Piercy V., Carter S. A., Lehner I., Smith S. A. Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature. 2000 Jul 27;406(6794):415–418. doi: 10.1038/35019082. [DOI] [PubMed] [Google Scholar]
  5. Clarke G., Collins R. A., Leavitt B. R., Andrews D. F., Hayden M. R., Lumsden C. J., McInnes R. R. A one-hit model of cell death in inherited neuronal degenerations. Nature. 2000 Jul 13;406(6792):195–199. doi: 10.1038/35018098. [DOI] [PubMed] [Google Scholar]
  6. Cottle C. A., Price E. O. Effects of the nonagouti pelage-color allele on the behavior of captive wild Norway rats (Rattus norvegicus). J Comp Psychol. 1987 Dec;101(4):390–394. [PubMed] [Google Scholar]
  7. Dinulescu D. M., Fan W., Boston B. A., McCall K., Lamoreux M. L., Moore K. J., Montagno J., Cone R. D. Mahogany (mg) stimulates feeding and increases basal metabolic rate independent of its suppression of agouti. Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12707–12712. doi: 10.1073/pnas.95.21.12707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gomi H., Ikeda T., Kunieda T., Itohara S., Prusiner S. B., Yamanouchi K. Prion protein (PrP) is not involved in the pathogenesis of spongiform encephalopathy in zitter rats. Neurosci Lett. 1994 Jan 31;166(2):171–174. doi: 10.1016/0304-3940(94)90478-2. [DOI] [PubMed] [Google Scholar]
  9. Gomi H., Inui K., Taniguchi H., Yoshikawa Y., Yamanouchi K. Edematous changes in the central nervous system of zitter rats with genetic spongiform encephalopathy. J Neuropathol Exp Neurol. 1990 May;49(3):250–259. doi: 10.1097/00005072-199005000-00006. [DOI] [PubMed] [Google Scholar]
  10. Gunn T. M., Miller K. A., He L., Hyman R. W., Davis R. W., Azarani A., Schlossman S. F., Duke-Cohan J. S., Barsh G. S. The mouse mahogany locus encodes a transmembrane form of human attractin. Nature. 1999 Mar 11;398(6723):152–156. doi: 10.1038/18217. [DOI] [PubMed] [Google Scholar]
  11. Hayssen V. Effects of the nonagouti coat-color allele on behavior of deer mice (Peromyscus maniculatus): a comparison with Norway rats (Rattus norvegicus). J Comp Psychol. 1997 Dec;111(4):419–423. doi: 10.1037/0735-7036.111.4.419. [DOI] [PubMed] [Google Scholar]
  12. He L., Gunn T. M., Bouley D. M., Lu X. Y., Watson S. J., Schlossman S. F., Duke-Cohan J. S., Barsh G. S. A biochemical function for attractin in agouti-induced pigmentation and obesity. Nat Genet. 2001 Jan;27(1):40–47. doi: 10.1038/83741. [DOI] [PubMed] [Google Scholar]
  13. Hein L., Barsh G. S., Pratt R. E., Dzau V. J., Kobilka B. K. Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. Nature. 1995 Oct 26;377(6551):744–747. doi: 10.1038/377744a0. [DOI] [PubMed] [Google Scholar]
  14. Hustad C. M., Perry W. L., Siracusa L. D., Rasberry C., Cobb L., Cattanach B. M., Kovatch R., Copeland N. G., Jenkins N. A. Molecular genetic characterization of six recessive viable alleles of the mouse agouti locus. Genetics. 1995 May;140(1):255–265. doi: 10.1093/genetics/140.1.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Inui T., Yamamura T., Yuasa H., Kawai Y., Okaniwa A., Serikawa T., Yamada J. The spontaneously epileptic rat (SER), a zitter*tremor double mutant rat: histopathological findings in the central nervous system. Brain Res. 1990 May 28;517(1-2):123–133. doi: 10.1016/0006-8993(90)91017-b. [DOI] [PubMed] [Google Scholar]
  17. Ito S., Fujita K. Microanalysis of eumelanin and pheomelanin in hair and melanomas by chemical degradation and liquid chromatography. Anal Biochem. 1985 Feb 1;144(2):527–536. doi: 10.1016/0003-2697(85)90150-2. [DOI] [PubMed] [Google Scholar]
  18. Ito S., Wakamatsu K. Chemical degradation of melanins: application to identification of dopamine-melanin. Pigment Cell Res. 1998 Apr;11(2):120–126. doi: 10.1111/j.1600-0749.1998.tb00721.x. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Kondo A., Sato Y., Nagara H. An ultrastructural study of oligodendrocytes in zitter rat: a new animal model for hypomyelination in the CNS. J Neurocytol. 1991 Nov;20(11):929–939. doi: 10.1007/BF01190470. [DOI] [PubMed] [Google Scholar]
  21. Kondo A., Sendoh S., Akazawa K., Sato Y., Nagara H. Early myelination in zitter rat: morphological, immunocytochemical and morphometric studies. Brain Res Dev Brain Res. 1992 Jun 19;67(2):217–228. doi: 10.1016/0165-3806(92)90222-i. [DOI] [PubMed] [Google Scholar]
  22. Kondo A., Sendoh S., Miyata K., Takamatsu J. Spongy degeneration in the zitter rat: ultrastructural and immunohistochemical studies. J Neurocytol. 1995 Jul;24(7):533–544. doi: 10.1007/BF01179978. [DOI] [PubMed] [Google Scholar]
  23. Kondo A., Sendoh S., Takamatsu J., Nagara H. The zitter rat: membranous abnormality in the Schwann cells of myelinated nerve fibers. Brain Res. 1993 Jun 4;613(1):173–179. doi: 10.1016/0006-8993(93)90471-x. [DOI] [PubMed] [Google Scholar]
  24. Kuramoto T., Kitada K., Inui T., Sasaki Y., Ito K., Hase T., Kawagachi S., Ogawa Y., Nakao K., Barsh G. S. Attractin/mahogany/zitter plays a critical role in myelination of the central nervous system. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):559–564. doi: 10.1073/pnas.98.2.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kuramoto T., Yamasaki K., Kondo A., Nakajima K., Yamada M., Serikawa T. Production of WTC.ZI-zi rat congenic strain and its pathological and genetic analyses. Exp Anim. 1998 Apr;47(2):75–81. doi: 10.1538/expanim.47.75. [DOI] [PubMed] [Google Scholar]
  26. Leighton P. A., Mitchell K. J., Goodrich L. V., Lu X., Pinson K., Scherz P., Skarnes W. C., Tessier-Lavigne M. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature. 2001 Mar 8;410(6825):174–179. doi: 10.1038/35065539. [DOI] [PubMed] [Google Scholar]
  27. Lowell B. B., S-Susulic V., Hamann A., Lawitts J. A., Himms-Hagen J., Boyer B. B., Kozak L. P., Flier J. S. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature. 1993 Dec 23;366(6457):740–742. doi: 10.1038/366740a0. [DOI] [PubMed] [Google Scholar]
  28. Lu X. y., Gunn T. M., Shieh K. r., Barsh G. S., Akil H., Watson S. J. Distribution of Mahogany/Attractin mRNA in the rat central nervous system. FEBS Lett. 1999 Nov 26;462(1-2):101–107. doi: 10.1016/s0014-5793(99)01494-5. [DOI] [PubMed] [Google Scholar]
  29. MAYER J. Decreased activity and energy balance in the hereditary obesity-diabetes syndrome of mice. Science. 1953 May 8;117(3045):504–505. doi: 10.1126/science.117.3045.504. [DOI] [PubMed] [Google Scholar]
  30. Mansuy I. M., Suter U. Mouse genetics in cell biology. Exp Physiol. 2000 Nov;85(6):661–679. [PubMed] [Google Scholar]
  31. Miller K. A., Gunn T. M., Carrasquillo M. M., Lamoreux M. L., Galbraith D. B., Barsh G. S. Genetic studies of the mouse mutations mahogany and mahoganoid. Genetics. 1997 Aug;146(4):1407–1415. doi: 10.1093/genetics/146.4.1407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nagle D. L., McGrail S. H., Vitale J., Woolf E. A., Dussault B. J., Jr, DiRocco L., Holmgren L., Montagno J., Bork P., Huszar D. The mahogany protein is a receptor involved in suppression of obesity. Nature. 1999 Mar 11;398(6723):148–152. doi: 10.1038/18210. [DOI] [PubMed] [Google Scholar]
  33. Ollmann M. M., Wilson B. D., Yang Y. K., Kerns J. A., Chen Y., Gantz I., Barsh G. S. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997 Oct 3;278(5335):135–138. doi: 10.1126/science.278.5335.135. [DOI] [PubMed] [Google Scholar]
  34. Ozeki H., Ito S., Wakamatsu K., Hirobe T. Chemical characterization of hair melanins in various coat-color mutants of mice. J Invest Dermatol. 1995 Sep;105(3):361–366. doi: 10.1111/1523-1747.ep12320792. [DOI] [PubMed] [Google Scholar]
  35. Rehm S., Mehraein P., Anzil A. P., Deerberg F. A new rat mutant with defective overhairs and spongy degeneration of the central nervous system: clinical and pathologic studies. Lab Anim Sci. 1982 Feb;32(1):70–73. [PubMed] [Google Scholar]
  36. Shimada M., Tritos N. A., Lowell B. B., Flier J. S., Maratos-Flier E. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature. 1998 Dec 17;396(6712):670–674. doi: 10.1038/25341. [DOI] [PubMed] [Google Scholar]
  37. Shutter J. R., Graham M., Kinsey A. C., Scully S., Lüthy R., Stark K. L. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev. 1997 Mar 1;11(5):593–602. doi: 10.1101/gad.11.5.593. [DOI] [PubMed] [Google Scholar]
  38. Williams G., Gill J. S., Lee Y. C., Cardoso H. M., Okpere B. E., Bloom S. R. Increased neuropeptide Y concentrations in specific hypothalamic regions of streptozocin-induced diabetic rats. Diabetes. 1989 Mar;38(3):321–327. doi: 10.2337/diab.38.3.321. [DOI] [PubMed] [Google Scholar]
  39. Xue B., Moustaid-N, Wilkison W. O., Zemel M. B. The agouti gene product inhibits lipolysis in human adipocytes via a Ca2+-dependent mechanism. FASEB J. 1998 Oct;12(13):1391–1396. [PubMed] [Google Scholar]
  40. Yang Y. K., Thompson D. A., Dickinson C. J., Wilken J., Barsh G. S., Kent S. B., Gantz I. Characterization of Agouti-related protein binding to melanocortin receptors. Mol Endocrinol. 1999 Jan;13(1):148–155. doi: 10.1210/mend.13.1.0223. [DOI] [PubMed] [Google Scholar]
  41. Ziotopoulou M., Mantzoros C. S., Hileman S. M., Flier J. S. Differential expression of hypothalamic neuropeptides in the early phase of diet-induced obesity in mice. Am J Physiol Endocrinol Metab. 2000 Oct;279(4):E838–E845. doi: 10.1152/ajpendo.2000.279.4.E838. [DOI] [PubMed] [Google Scholar]

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