Metabolic regulation of the ultradian oscillator Hes1 by reactive oxygen species

J Mol Biol. 2015 May 22;427(10):1887-902. doi: 10.1016/j.jmb.2015.03.007. Epub 2015 Mar 18.


Ultradian oscillators are cyclically expressed genes with a period of less than 24h, found in the major signalling pathways. The Notch effector hairy and enhancer of split Hes genes are ultradian oscillators. The physiological signals that synchronise and entrain Hes oscillators remain poorly understood. We investigated whether cellular metabolism modulates Hes1 cyclic expression. We demonstrated that, in mouse myoblasts (C2C12), Hes1 oscillation depends on reactive oxygen species (ROS), which are generated by the mitochondria electron transport chain and by NADPH oxidases NOXs. In vitro, the regulation of Hes1 by ROS occurs via the calcium-mediated signalling. The modulation of Hes1 by ROS was relevant in vivo, since perturbing ROS homeostasis was sufficient to alter Medaka (Oryzias latipes) somitogenesis, a process that is dependent on Hes1 ultradian oscillation during embryo development. Moreover, in a Medaka model for human microphthalmia with linear skin lesions syndrome, in which mitochondrial ROS homeostasis was impaired, we documented important somitogenesis defects and the deregulation of Hes homologues genes involved in somitogenesis. Notably, both molecular and developmental defects were rescued by antioxidant treatments. Our studies provide the first evidence of a coupling between cellular redox metabolism and an ultradian biological oscillator with important pathophysiological implication for somitogenesis.

Keywords: hairy and enhancer of split (Hes); human genetic mitochondrial diseases; reactive oxygen species; somitogenesis; ultradian clock.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Biological Clocks / physiology*
  • Calcium / metabolism
  • Cells, Cultured
  • Disease Models, Animal*
  • Electron Transport Complex III / metabolism
  • Embryo, Nonmammalian / metabolism
  • Gene Expression Regulation, Developmental*
  • Homeodomain Proteins / physiology*
  • Humans
  • In Situ Hybridization
  • Mice
  • Microphthalmos / metabolism
  • Microphthalmos / pathology
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Myoblasts / cytology
  • Myoblasts / metabolism
  • NADPH Oxidases / metabolism
  • Oryzias / embryology
  • Oryzias / genetics*
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Skin Abnormalities / metabolism
  • Skin Abnormalities / pathology
  • Somites / embryology
  • Somites / metabolism
  • Somites / pathology*
  • Syndrome
  • Transcription Factor HES-1


  • Antioxidants
  • Basic Helix-Loop-Helix Transcription Factors
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • Reactive Oxygen Species
  • Transcription Factor HES-1
  • NADPH Oxidases
  • Electron Transport Complex III
  • Calcium