Abstract
SummaryRetinal 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.
Highlights
There has been remarkable progress in our understanding of the complex intracellular mechanisms that generate and regulate circadian rhythms across multiple species
Retinal photoreceptors entrain the circadian system to the solar day
By analyzing the lightregulated transcriptome of the suprachiasmatic nuclei (SCN), we have identified a key role for salt inducible kinase 1 (SIK1) and cAMP response element binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) in clock re-setting
Summary
There has been remarkable progress in our understanding of the complex intracellular mechanisms that generate and regulate circadian rhythms across multiple species. The molecular clock arises from a transcriptional translational-feedback loop, consisting of the transcription factors CLOCK and BMAL1 that drive the expression of their regulators, PERIOD and CRYPTOCHROME (Reppert and Weaver, 2002). These elements form part of an autoregulatory-feedback loop, the period of which is approximately 24 hr. A growing body of evidence demonstrates that rods, and the different classes of cone photoreceptor, can complement the role of the pRGCs in circadian entrainment by expanding the irradiance range of the response and in the detection of light transitions (Lall et al, 2010; van Oosterhout et al, 2012)
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