Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling

Neuron. 2013 Aug 21;79(4):712-24. doi: 10.1016/j.neuron.2013.06.026.

Abstract

Protein synthesis is critical for circadian clock function, but little is known of how translational regulation controls the master pacemaker in mammals, the suprachiasmatic nucleus (SCN). Here we demonstrate that the pivotal translational repressor, the eukaryotic translational initiation factor 4E binding protein 1 (4E-BP1), is rhythmically regulated via the mechanistic target of rapamycin (mTOR) signaling in the SCN and preferentially represses vasoactive intestinal peptide (Vip) mRNA translation. Knockout (KO) of Eif4ebp1 (gene encoding 4E-BP1) leads to upregulation of VIP and higher amplitude of molecular rhythms in the SCN. Consequently, the 4E-BP1 null mice exhibit accelerated re-entrainment to a shifted light/dark cycle and are more resistant to the rhythm-disruptive effects of constant light. Conversely, in Mtor(+/-) mice VIP expression is decreased and susceptibility to the effects of constant light is increased. These results reveal a key role for mTOR/4E-BP1-mediated translational control in regulating entrainment and synchrony of the master clock.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Anthraquinones / pharmacology
  • Butadienes / pharmacology
  • Carrier Proteins / physiology*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Circadian Rhythm / physiology*
  • Enzyme Inhibitors / pharmacology
  • Eukaryotic Initiation Factors
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Indoles / pharmacology
  • Light
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitriles / pharmacology
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • Phosphoproteins / deficiency
  • Phosphoproteins / physiology*
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Purines / pharmacology
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Sirolimus / pharmacology
  • Suprachiasmatic Nucleus / metabolism*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / physiology*
  • Vasoactive Intestinal Peptide / genetics
  • Vasoactive Intestinal Peptide / metabolism

Substances

  • 1,5-bis((2-(methylamino)ethyl)amino)-4,8-dihydroxyanthracene-9,10-dione
  • Adaptor Proteins, Signal Transducing
  • Anthraquinones
  • Butadienes
  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Enzyme Inhibitors
  • Eukaryotic Initiation Factors
  • Indoles
  • Nitriles
  • Per1 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Phosphoproteins
  • Purines
  • RNA, Messenger
  • RNA, Small Interfering
  • U 0126
  • Vasoactive Intestinal Peptide
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • PP242
  • Sirolimus