title: The CRTC1-SIK1 pathway regulates entrainment of the circadian clock.
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.
authors.affiliation: 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.
authors.forename: Aarti
authors.initials: A
authors.lastname: Jagannath
authors.affiliation: 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.
authors.forename: Rachel
authors.initials: R
authors.lastname: Butler
authors.affiliation: 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.
authors.forename: Sofia I H
authors.initials: SIH
authors.lastname: Godinho
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Couch
authors.affiliation: 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.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Brown
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Sridhar R
authors.initials: SR
authors.lastname: Vasudevan
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Galvin Life Sciences Center, Notre Dame, IN 46556, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Flanagan
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Anthony
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Grant C
authors.initials: GC
authors.lastname: Churchill
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
authors.forename: Matthew J A
authors.initials: MJA
authors.lastname: Wood
authors.affiliation: pRED Pharma Research and Development F. Hoffmann-La Roche, 4070 Basel, Switzerland.
authors.forename: Guido
authors.initials: G
authors.lastname: Steiner
authors.affiliation: pRED Pharma Research and Development F. Hoffmann-La Roche, 4070 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Ebeling
authors.affiliation: Axolabs GmbH Fritz-Hornschuch-Straße 9, 95326 Kulmbach, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hossbach
authors.affiliation: pRED Pharma Research and Development F. Hoffmann-La Roche, 4070 Basel, Switzerland.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Galvin Life Sciences Center, Notre Dame, IN 46556, USA.
authors.forename: Giles E
authors.initials: GE
authors.lastname: Duffield
authors.affiliation: pRED Pharma Research and Development F. Hoffmann-La Roche, 4070 Basel, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gatti
authors.affiliation: 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.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Hankins
authors.affiliation: 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.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Foster
authors.affiliation: 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.
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Peirson
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D057906:Circadian Clocks; D002940:Circadian Rhythm; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017299:Rod Opsins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000099210:Melanopsin
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D017299:Rod Opsins; D014157:Transcription Factors; D000099210:Melanopsin; C519509:Crtc1 protein, mouse; C495376:Sik1 protein, mouse