Metabolic Regulation of the Ultradian Oscillator Hes1 by Reactive Oxygen Species. Issue 10 (22nd May 2015)

• Record Type: Journal Article
• Authors: Ventre, Simona; Indrieri, Alessia; Fracassi, Chiara; Franco, Brunella; Conte, Ivan; Cardone, Luca; di Bernardo, Diego
• Is Part Of: Journal of molecular biology. Volume 427:Issue 10(2015:May 15)
• Page Start: 1887
• Page End: 1902
• Publication Date: 2015-05-22
• Subjects: ROS reactive oxygen species -- ETC electron transport chain -- MLS microphthalmia with linear skin lesions -- PSM presomitic mesoderm -- MAPK mitogen-activated protein kinase -- SS serum stimulation -- qRT-PCR quantitative real-time PCR -- NAC N-acetyl cysteine -- DPI diphenylene iodonium -- NICD Notch intracellular domain -- FBS foetal bovine serum -- ISH in situ hybridization; hairy and enhancer of split (Hes) -- reactive oxygen species -- ultradian clock -- somitogenesis -- human genetic mitochondrial diseases; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2015.03.007
• Languages: English
• ISSNs: 0022-2836

Abstract

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. Graphical abstract: Highlights: ROS control the ultradian oscillation of Hes1 . ROS generated by mitochondrial complex III and NOX control Hes1 oscillation. ROS control the segmentation clock in Medaka fish. A Medaka model of a human disease involving electron transport chain shows somitogenesis defects.