Reports

The After-Hours Mutant Reveals a Role for Fbxl3 in Determining Mammalian Circadian Period

Sofia I. H. Godinho,^1* Elizabeth S. Maywood,^2* Linda Shaw,^1* Valter Tucci,¹ Alun R. Barnard,¹ Luca Busino,³ Michele Pagano,³ Rachel Kendall,¹ Mohamed M. Quwailid,¹ M. Rosario Romero,¹ John O'Neill,² Johanna E. Chesham,² Debra Brooker,¹ Zuzanna Lalanne,¹ Michael H. Hastings,² Patrick M. Nolan¹

By screening N-ethyl-N-nitrosourea–mutagenized animals for alterations in rhythms of wheel-running activity, we identified a mouse mutation, after hours (Afh). The mutation, a Cys³⁵⁸Ser substitution in Fbxl3, an F-box protein with leucine-rich repeats, results in long free-running rhythms of about 27 hours in homozygotes. Circadian transcriptional and translational oscillations are attenuated in Afh mice. The Afh allele significantly affected Per2 expression and delayed the rate of Cry protein degradation in Per2::Luciferase tissue slices. Our in vivo and in vitro studies reveal a central role for Fbxl3 in mammalian circadian timekeeping.

¹ Medical Research Council (MRC) Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
² MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Road, Cambridge CB2 2QH, UK.
³ Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, NY 10016, USA.

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: p.nolan{at}har.mrc.ac.uk

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Peripheral Circadian Oscillators: Interesting Mechanisms and Powerful Tools.

L. CUNINKOVA and S. A. BROWN (2008)
Ann. N.Y. Acad. Sci. 1129, 358-370
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Evidence for an Overlapping Role of CLOCK and NPAS2 Transcription Factors in Liver Circadian Oscillators.

C. Bertolucci, N. Cavallari, I. Colognesi, J. Aguzzi, Z. Chen, P. Caruso, A. Foa, G. Tosini, F. Bernardi, and M. Pinotti (2008)
Mol. Cell. Biol. 28, 3070-3075
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The green yeast uses its plant-like clock to regulate its animal-like tail.

M. Brunner and M. Merrow (2008)
Genes & Dev. 22, 825-831
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A systematic forward genetic analysis identified components of the Chlamydomonas circadian system.

T. Matsuo, K. Okamoto, K. Onai, Y. Niwa, K. Shimogawara, and M. Ishiura (2008)
Genes & Dev. 22, 918-930
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Fbxw15/Fbxo12J Is an F-Box Protein-Encoding Gene Selectively Expressed in Oocytes of the Mouse Ovary.

E. De La Chesnaye, B. Kerr, A. Paredes, H. Merchant-Larios, J. P. Mendez, and S. R. Ojeda (2008)
Biol Reprod 78, 714-725
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Probing the Relative Importance of Molecular Oscillations in the Circadian Clock.

X. Zheng and A. Sehgal (2008)
Genetics 178, 1147-1155
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Minireview: The Circadian Clockwork of the Suprachiasmatic Nuclei Analysis of a Cellular Oscillator that Drives Endocrine Rhythms.

E. S. Maywood, J. S. O'Neill, J. E. Chesham, and M. H. Hastings (2007)
Endocrinology 148, 5624-5634
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Circadian clocks: regulators of endocrine and metabolic rhythms.

M. Hastings, J. S O'Neill, and E. S Maywood (2007)
J. Endocrinol. 195, 187-198
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Highlights From The Literature.

(2007)
Physiology 22, 299-302
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Peripheral Circadian Clocks in the Vasculature.

D. F. Reilly, E. J. Westgate, and G. A. FitzGerald (2007)
Arterioscler. Thromb. Vasc. Biol. 27, 1694-1705
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SCFFbxl3 Controls the Oscillation of the Circadian Clock by Directing the Degradation of Cryptochrome Proteins.

L. Busino, F. Bassermann, A. Maiolica, C. Lee, P. M. Nolan, S. I. H. Godinho, G. F. Draetta, and M. Pagano (2007)
Science 316, 900-904
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