Aarti Jagannath 1 , 5 , 7 , Rachel Butler 1 , 5 , 7 , Sofia I.H. Godinho 1 , 5 , Yvonne Couch 2 , Laurence A. Brown 1 , Sridhar R. Vasudevan 2 , Kevin C. Flanagan 3 , Daniel Anthony 2 , Grant C. Churchill 2 , Matthew J.A. Wood 4 , Guido Steiner 5 , Martin Ebeling 5 , Markus Hossbach 6 , Joseph G. Wettstein 5 , Giles E. Duffield 3 , Silvia Gatti 5 , Mark W. Hankins 1 , Russell G. Foster 1 , ∗ , Stuart N. Peirson 1 , ∗∗
29 August 2013
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.
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.