Abstract
In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and it orchestrates peripheral clocks in the whole body to organize physiological and behavioral rhythms. Light-induced phase-shift of the SCN clock enables synchronization of the circadian clock system with 24-h environmental light/dark cycle. We previously found that adenosine deaminase acting on RNA 2 (Adar2), an A-to-I RNA editing enzyme catalyzing rhythmic A-to-I RNA editing, governs a wide range of mRNA rhythms in the mouse liver and regulates the circadian behavior. In brain, ADAR2-mediated A-to-I RNA editing was reported to occur in various transcripts encoding ion channels and neurotransmitter receptors, which could influence neuronal function of the SCN. Here we show that ADAR2 plays a crucial role for light-induced phase-shift of the circadian clock. Intriguingly, exposure of Adar2-knockout mice to a light pulse at late night caused an aberrant phase-advance of the locomotor rhythms. By monitoring the bioluminescence rhythms of the mutant SCN slices, we found that a phase-advance induced by treatment with pituitary adenylyl cyclase-activating polypeptide (PACAP) was markedly attenuated. The present study suggests that A-to-I RNA editing in the SCN regulates a proper phase response to light in the mouse circadian system.
Highlights
The circadian clock is a self-sustained time-measuring system that generates daily rhythms of behavior, physiology and gene expression with a period of approximately 24 h1
In control mice suprachiasmatic nucleus (SCN), direct sequencing analysis detected substantial levels of A-to-I RNA editing in the transcripts coding ion channels and receptors, such as glutamate receptor ionotropic AMPA2 (Gria2), glutamate receptor ionotropic kainate 2 (Grik2), calcium channel voltage-dependent L type alpha 1D subunit (Cacna1d), potassium voltage-gated channel shaker-related subfamily member 1 (Kcna1), 5-hydroxytryptamine receptor 2 C (Htr2c) and gamma-aminobutyric acid A receptor subunit alpha 3 (Gabra3) (Fig. 1a, Supplementary Fig. 1a)
Our results indicated that ADAR2 regulates considerable levels of the A-to-I editing of the mRNAs encoding these ion channels and receptors expressed in the SCN
Summary
The circadian clock is a self-sustained time-measuring system that generates daily rhythms of behavior, physiology and gene expression with a period of approximately 24 h1. Photic stimulation received by the retina at early night induces phase-delay of the SCN clock, while the stimulation at late night induces phase-advance. These light-induced bidirectional phase-shifts of the circadian clock are thought to be evoked by acute induction of a subset of clock gene expression[3], but the signaling pathway directing either phase-advance or phase-delay is still elusive. Lateral sclerosis (ALS)[27] and glioblastoma multiforme[28] These studies prompted us to investigate a role of ADAR2 for the circadian clock in the SCN. Our data demonstrate an important role of ADAR2 in regulating the phase-advance of the circadian rhythms and suggest that RNA modification regulates the light input pathway in the SCN
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