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

Nat Cell Biol. 2008 Dec;10(12):1463-9. doi: 10.1038/ncb1806. Epub 2008 Nov 23.

Abstract

The circadian clock is reset by external time cues for synchronization to environmental changes. In mammals, the light-input signalling pathway mediated by Per gene induction has been extensively studied. On the other hand, little is known about resetting mechanisms that are independent of Per induction. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism*
  • Alkalies / pharmacology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biological Clocks / drug effects
  • Biological Clocks / genetics*
  • Cells, Cultured
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / genetics*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation / drug effects
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Hydrogen-Ion Concentration / drug effects
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Signal Transduction* / drug effects
  • Transforming Growth Factor beta / metabolism*

Substances

  • Alkalies
  • Basic Helix-Loop-Helix Transcription Factors
  • Bhlhe40 protein, mouse
  • Bhlhe40 protein, rat
  • Homeodomain Proteins
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Activins