Abstract
The mammalian master circadian pacemaker within the suprachiasmatic nucleus (SCN) maintains tight entrainment to the 24 hr light/dark cycle via a sophisticated clock-gated rhythm in the responsiveness of the oscillator to light. A central event in this light entrainment process appears to be the rapid induction of gene expression via the ERK/MAPK pathway. Here, we used RNA array-based profiling in combination with pharmacological disruption methods to examine the contribution of ERK/MAPK signaling to light-evoked gene expression. Transient photic stimulation during the circadian night, but not during the circadian day, triggered marked changes in gene expression, with early-night light predominately leading to increased gene expression and late-night light predominately leading to gene downregulation. Functional analysis revealed that light-regulated genes are involved in a diversity of physiological processes, including DNA transcription, RNA translation, mRNA processing, synaptic plasticity and circadian timing. The disruption of MAPK signaling led to a marked reduction in light-evoked gene regulation during the early night (32/52 genes) and late night (190/191 genes); further, MAPK signaling was found to gate gene expression across the circadian cycle. Together, these experiments reveal potentially important insights into the transcriptional-based mechanisms by which the ERK/MAPK pathway regulates circadian clock timing and light-evoked clock entrainment.
Highlights
In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master circadian oscillator
After two days in dark/12h dark (DD), mice were exposed to light (100 lux) for 10 minutes at one of three time points: mid-day, corresponding to zeitgeber time 4 (ZT 4), early night, corresponding to ZT15, or late night, corresponding to ZT 22; mice were returned to darkness for 10 minutes and sacrificed (Fig 1A)
As a starting point for this study, we provide data that both supports and extends previous studies showing that, 1) photic stimulation leads to rapid ERK activation, 2) activation is restricted to the night time domain and 3) in vivo MEK inhibition potently suppresses MAPK activity and uncouples the clock from light
Summary
The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master circadian oscillator. The rhythm generated by the SCN sets the phasing and regulates the synchrony of peripheral oscillator populations found in every organ system of the body [1, 2]. Clock gene oscillations drive the rhythmic expression of thousands of clock-controlled genes, which, in turn, underlies the biochemical processes that give rise to rhythms in cellular physiology [3,4,5,6]. The phasing of the SCN oscillator is tightly regulated by the daily light cycle. This lightentrainment process is mediated by a monosynaptic input (via the retinohypothalamic tract)
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