Activation of TGF-β/activin signalling resets the circadian clock through rapid induction of Dec1 transcripts

The circadian clock is reset by external time cues for synchronization to environmental changes(1). In mammals, the light-input signalling pathway mediated by Per gene induction has been extensively studied(2,3). On the other hand, little is known about resetting mechanisms that are independent of Per induction(4-6). Here we show that activation of activin receptor-like kinase (ALK), triggered by TGF-beta, activin or alkali signals, evoked resetting of the cellular clock independently of Per induction. The resetting was mediated by an immediate-early induction of Dec1, a gene whose physiological role in the function of the circadian clock has been unclear. Acute Dec1 induction was a prerequisite for ALK-mediated resetting and upregulation was dependent on SMAD3, which was phosphorylated for activation in response to the resetting stimuli. Intraperitoneal injection of TGF-beta into wild-type or Dec1-deficient mice demonstrated that Dec1 has an essential role in phase-shift of clock gene expression in the kidney and adrenal gland. These results indicate that ALK-SMAD3-Dec1 signalling provides an input pathway in the mammalian molecular clock.