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      The CRTC1-SIK1 Pathway Regulates Entrainment of the Circadian Clock

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          Summary

          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.

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          Highlights

          • Nocturnal light induces widespread transcriptional changes in the SCN

          • The CRTC1-SIK1 cascade regulates entrainment of the circadian clock

          • Negative feedback by SIK1 limits the effects of light on the clock

          • Homeostatic regulation of entrainment ensures gradual adaptation to a new time zone

          Abstract

          A negative-feedback loop involving the kinase SIK1 and the transcriptional coactivator CRTC1 delays re-entrainment of the circadian clock to new time zones, causing jet lag. Remarkably, inhibition of SIK1 allows rapid re-entrainment after an experimental jet lag protocol in mice.

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          Most cited references46

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          Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice.

          In the mammalian retina, besides the conventional rod-cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive. Furthermore, pupil reflex, light-induced phase delays of the circadian clock and period lengthening of the circadian rhythm in constant light are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.
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            Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice.

            In the mammalian retina, a small subset of retinal ganglion cells (RGCs) are intrinsically photosensitive, express the opsin-like protein melanopsin, and project to brain nuclei involved in non-image-forming visual functions such as pupillary light reflex and circadian photoentrainment. We report that in mice with the melanopsin gene ablated, RGCs retrograde-labeled from the suprachiasmatic nuclei were no longer intrinsically photosensitive, although their number, morphology, and projections were unchanged. These animals showed a pupillary light reflex indistinguishable from that of the wild type at low irradiances, but at high irradiances the reflex was incomplete, a pattern that suggests that the melanopsin-associated system and the classical rod/cone system are complementary in function.
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              A serum shock induces circadian gene expression in mammalian tissue culture cells.

              The treatment of cultured rat-1 fibroblasts or H35 hepatoma cells with high concentrations of serum induces the circadian expression of various genes whose transcription also oscillates in living animals. Oscillating genes include rper1 and rper2 (rat homologs of the Drosophila clock gene period), and the genes encoding the transcription factors Rev-Erb alpha, DBP, and TEF. In rat-1 fibroblasts, up to three consecutive daily oscillations with an average period length of 22.5 hr could be recorded. The temporal sequence of the various mRNA accumulation cycles is the same in cultured cells and in vivo. The serum shock of rat-1 fibroblasts also results in a transient stimulation of c-fos and rper expression and thus mimics light-induced immediate-early gene expression in the suprachiasmatic nucleus.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                29 August 2013
                29 August 2013
                : 154
                : 5
                : 1100-1111
                Affiliations
                [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
                [2 ]Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
                [3 ]Department of Biological Sciences, University of Notre Dame, Galvin Life Sciences Center, Notre Dame, IN 46556, USA
                [4 ]Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
                [5 ]pRED Pharma Research and Development F. Hoffmann-La Roche, 4070 Basel, Switzerland
                [6 ]Axolabs GmbH Fritz-Hornschuch-Straße 9, 95326 Kulmbach, Germany
                Author notes
                []Corresponding author russell.foster@ 123456eye.ox.ac.uk
                [∗∗ ]Corresponding author stuart.peirson@ 123456eye.ox.ac.uk
                [7]

                These authors contributed equally to this work

                Article
                S0092-8674(13)00961-6
                10.1016/j.cell.2013.08.004
                3898689
                23993098
                76017fea-af24-4242-833f-48091006da1b
                © 2013 ELL & Excerpta Medica.

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 8 January 2013
                : 24 May 2013
                : 29 July 2013
                Categories
                Article

                Cell biology
                Cell biology

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