Metabolic regulation of the ultradian oscillator hes1 by Reactive Oxygen Species

Simona Ventre, Alessia Indrieri, Chiara Fracassi, Brunella Franco, Ivan Conte, Luca Cardone, Diego Di Bernardo

Research output: Contribution to journalArticlepeer-review

Abstract

Ultradian oscillators are cyclically expressed genes with a period of less than 24 h, 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.

Original languageEnglish
Pages (from-to)1887-1902
Number of pages16
JournalJournal of Molecular Biology
Volume427
Issue number10
DOIs
Publication statusPublished - May 22 2015

Keywords

  • hairy and enhancer of split (Hes)
  • human genetic mitochondrial diseases
  • ltradian clock
  • omitogenesis
  • reactive oxygen species

ASJC Scopus subject areas

  • Molecular Biology

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