Cell
Volume 154, Issue 5, 29 August 2013, Pages 1100-1111
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Article
The CRTC1-SIK1 Pathway Regulates Entrainment of the Circadian Clock

https://doi.org/10.1016/j.cell.2013.08.004Get rights and content
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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

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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These authors contributed equally to this work