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Cell. 2013 Aug 29;154(5):1100-1111. doi: 10.1016/j.cell.2013.08.004.

The CRTC1-SIK1 pathway regulates entrainment of the circadian clock.

Author information

1
Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), University of Oxford, Levels 5-6 West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK; pRED Pharma Research and Development F. Hoffmann-La Roche, 4070 Basel, Switzerland.
2
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
3
Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), University of Oxford, Levels 5-6 West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
4
Department of Biological Sciences, University of Notre Dame, Galvin Life Sciences Center, Notre Dame, IN 46556, USA.
5
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
6
pRED Pharma Research and Development F. Hoffmann-La Roche, 4070 Basel, Switzerland.
7
Axolabs GmbH Fritz-Hornschuch-Straße 9, 95326 Kulmbach, Germany.
8
Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), University of Oxford, Levels 5-6 West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK. Electronic address: russell.foster@eye.ox.ac.uk.
9
Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), University of Oxford, Levels 5-6 West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK. Electronic address: stuart.peirson@eye.ox.ac.uk.

Abstract

Retinal photoreceptors entrain the circadian system to the solar day. This photic resetting involves cAMP response element binding protein (CREB)-mediated upregulation of Per genes within individual cells of the suprachiasmatic nuclei (SCN). Our detailed understanding of this pathway is poor, and it remains unclear why entrainment to a new time zone takes several days. By analyzing the light-regulated transcriptome of the SCN, we have identified a key role for salt inducible kinase 1 (SIK1) and CREB-regulated transcription coactivator 1 (CRTC1) in clock re-setting. An entrainment stimulus causes CRTC1 to coactivate CREB, inducing the expression of Per1 and Sik1. SIK1 then inhibits further shifts of the clock by phosphorylation and deactivation of CRTC1. Knockdown of Sik1 within the SCN results in increased behavioral phase shifts and rapid re-entrainment following experimental jet lag. Thus SIK1 provides negative feedback, acting to suppress the effects of light on the clock. This pathway provides a potential target for the regulation of circadian rhythms.

PMID:
23993098
PMCID:
PMC3898689
DOI:
10.1016/j.cell.2013.08.004
[Indexed for MEDLINE]
Free PMC Article

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