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Neuron. 2008 Apr 10;58(1):78-88. doi: 10.1016/j.neuron.2008.01.019.

Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins.

Author information

1
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
2
MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Rd. Cambridge CB2 2QH, U.K.
3
Department of Pediatrics, University of Utah, Salt Lake City, Utah 84112, USA.
4
Howard Hughes Medical Institute, Dept. of Neurobiology & Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3520, USA.
5
Program in Cancer and Stem Cell Biology, Duke/NUS Graduate Medical School Singapore, 2 Jalan Bukit Merah, Singapore 169547.
#
Contributed equally

Abstract

The intrinsic period of circadian clocks is their defining adaptive property. To identify the biochemical mechanisms whereby casein kinase1 (CK1) determines circadian period in mammals, we created mouse null and tau mutants of Ck1 epsilon. Circadian period lengthened in CK1epsilon-/-, whereas CK1epsilon(tau/tau) shortened circadian period of behavior in vivo and suprachiasmatic nucleus firing rates in vitro, by accelerating PERIOD-dependent molecular feedback loops. CK1epsilon(tau/tau) also accelerated molecular oscillations in peripheral tissues, revealing its global role in circadian pacemaking. CK1epsilon(tau) acted by promoting degradation of both nuclear and cytoplasmic PERIOD, but not CRYPTOCHROME, proteins. Together, these whole-animal and biochemical studies explain how tau, as a gain-of-function mutation, acts at a specific circadian phase to promote degradation of PERIOD proteins and thereby accelerate the mammalian clockwork in brain and periphery.

PMID:
18400165
PMCID:
PMC3756141
DOI:
10.1016/j.neuron.2008.01.019
[Indexed for MEDLINE]
Free PMC Article

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