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The imprinted gene Magel2 regulates normal circadian output

Nature Genetics volume 39, pages 12661272 (2007) | Download Citation



Mammalian circadian rhythms of activity are generated within the suprachiasmatic nucleus (SCN). Transcripts from the imprinted, paternally expressed Magel2 gene, which maps to the chromosomal region associated with Prader-Willi Syndrome (PWS), are highly enriched in the SCN. The Magel2 message is circadianly expressed and peaks during the subjective day. Mice deficient in Magel2 expression entrain to light cycles and express normal running-wheel rhythms, but with markedly reduced amplitude of activity and increased daytime activity. These changes are associated with reductions in food intake and male fertility. Orexin levels and orexin-positive neurons in the lateral hypothalamus are substantially reduced, suggesting that some of the consequences of Magel2 loss are mediated through changes in orexin signaling. The robust rhythmicity of Magel2 expression in the SCN and the altered behavioral rhythmicity of null mice reveal Magel2 to be a clock-controlled circadian output gene whose disruption results in some of the phenotypes characteristic of PWS.

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This work was supported by the Intramural Research Program of the National Cancer Institute, NIH grants MH63104 (EDH) and EY14988, and the Culpeper Medical Scientist Award of the Rockefeller Brothers Foundation (to R.N.V.G.). We thank R. Seeley for advice, R. Awashti for help in the fertility assays, and R. Frederickson for help in preparation of the figures.

Author information

Author notes

    • Colin L Stewart

    Present address: Institute for Medical Biology, #03-03 Proteos, 61 Biopolis Drive, Singapore 113867, Singapore.


  1. Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, Maryland 21702, USA.

    • Serguei V Kozlov
    •  & Colin L Stewart
  2. Department of Biology, Washington University, St. Louis, Missouri 63130, USA.

    • James W Bogenpohl
    •  & Erik D Herzog
  3. Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

    • Maureen P Howell
    •  & Louis J Muglia
  4. Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.

    • Rachel Wevrick
  5. Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.

    • Satchin Panda
  6. Genomics Institute of Novartis Research Foundation, La Jolla, California 92121, USA.

    • John B Hogenesch
  7. Departments of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

    • Louis J Muglia
  8. Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

    • Russell N Van Gelder


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R.N.V.G., S.V.K., E.D.H., R.W., J.B.H., L.J.M. and C.L.S. designed the experiments, S.V.K., S.P., M.P.H. and J.W.B. performed the experiments, and R.V.G., E.D.H. and C.L.S. wrote the paper.

Note: Supplementary information is available on the Nature Genetics website.

Corresponding author

Correspondence to Colin L Stewart.

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