TY - JOUR
T1 - Setting Clock Speed in Mammals
T2 - The CK1ε tau Mutation in Mice Accelerates Circadian Pacemakers by Selectively Destabilizing PERIOD Proteins
AU - Meng, Qing Jun
AU - Logunova, Larisa
AU - Maywood, Elizabeth S.
AU - Gallego, Monica
AU - Lebiecki, Jake
AU - Brown, Timothy M.
AU - Sládek, Martin
AU - Semikhodskii, Andrei S.
AU - Glossop, Nicholas R J
AU - Piggins, Hugh D.
AU - Chesham, Johanna E.
AU - Bechtold, David A.
AU - Yoo, Seung Hee
AU - Takahashi, Joseph S.
AU - Virshup, David M.
AU - Boot-Handford, Raymond P.
AU - Hastings, Michael H.
AU - Loudon, Andrew S I
N1 - Funding Information:
We thank Tracey Butcher, Graham Morrissey, Emma Owens, Sarah Atkinson, Helen Lydon, Jian Li, Julie Gibbs, and Shin Yamazaki for technical assistance. We thank Russell Foster, Owen Jones, and Rob Lucas for comments on the manuscript, Simon Luckman for access to the metabolic monitoring equipment (CLAMS), and Andrew Millar for BRASS software package, Masahiro Ishiura for RAP software package. We thank A. Kramer for kind provision of research materials. The project was supported by the Biotechnology and Biological Sciences Research Council and Medical Research Council of the UK for funding.
PY - 2008/4/10
Y1 - 2008/4/10
N2 - 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 CK1ε-/-, whereas CK1εtau/tau shortened circadian period of behavior in vivo and suprachiasmatic nucleus firing rates in vitro, by accelerating PERIOD-dependent molecular feedback loops. CK1εtau/tau also accelerated molecular oscillations in peripheral tissues, revealing its global role in circadian pacemaking. CK1εtau 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.
AB - 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 CK1ε-/-, whereas CK1εtau/tau shortened circadian period of behavior in vivo and suprachiasmatic nucleus firing rates in vitro, by accelerating PERIOD-dependent molecular feedback loops. CK1εtau/tau also accelerated molecular oscillations in peripheral tissues, revealing its global role in circadian pacemaking. CK1εtau 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.
KW - MOLNEURO
KW - SYSNEURO
UR - http://www.scopus.com/inward/record.url?scp=41549142176&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41549142176&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2008.01.019
DO - 10.1016/j.neuron.2008.01.019
M3 - Article
C2 - 18400165
AN - SCOPUS:41549142176
SN - 0896-6273
VL - 58
SP - 78
EP - 88
JO - Neuron
JF - Neuron
IS - 1
ER -