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The imprinted gene Magel2 regulates normal circadian output

Nature Genetics volume 39, pages 1266–1272 (2007)Cite this article

Abstract

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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Figure 1: Expression patterns of the Magel2 transcript, visualized using LacZ histochemistry, show both the paternal expression of Magel2 in vivo and the tissue specificity of Magel2 expression in the embryonic and adult nervous systems.
Figure 2: CNS Magel2 transcript levels change during circadian cycles, and loss of Magel2 expression affects activity cycles.
Figure 3: Breeding and feeding behavior is altered in Magel2m+/p− mice.
Figure 4: Orexin expression is reduced in Magel2-deficient animals.

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Acknowledgements

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.

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Author notes

  1. Colin L Stewart

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

Authors and Affiliations

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

    Serguei V Kozlov & Colin L Stewart

  2. Department of Biology, Washington University, St. Louis, 63130, Missouri, USA

    James W Bogenpohl & Erik D Herzog

  3. Department of Pediatrics, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Maureen P Howell & Louis J Muglia

  4. Department of Medical Genetics, University of Alberta, Edmonton, T6G 2H7, Alberta, Canada

    Rachel Wevrick

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

    Satchin Panda

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

    John B Hogenesch

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

    Louis J Muglia

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

    Russell N Van Gelder

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Contributions

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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Supplementary Figures 1–3, Supplementary Tables 1–4 (PDF 451 kb)

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Kozlov, S., Bogenpohl, J., Howell, M. et al. The imprinted gene Magel2 regulates normal circadian output. Nat Genet 39, 1266–1272 (2007). https://doi.org/10.1038/ng2114

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