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 language | English |
|---|---|
| Pages (from-to) | 1887-1902 |
| Number of pages | 16 |
| Journal | Journal of Molecular Biology |
| Volume | 427 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - May 22 2015 |
Fingerprint
Keywords
- hairy and enhancer of split (Hes)
- human genetic mitochondrial diseases
- ltradian clock
- omitogenesis
- reactive oxygen species
ASJC Scopus subject areas
- Molecular Biology
Cite this
Metabolic regulation of the ultradian oscillator hes1 by Reactive Oxygen Species. / Ventre, Simona; Indrieri, Alessia; Fracassi, Chiara; Franco, Brunella; Conte, Ivan; Cardone, Luca; Di Bernardo, Diego.
In: Journal of Molecular Biology, Vol. 427, No. 10, 22.05.2015, p. 1887-1902.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Metabolic regulation of the ultradian oscillator hes1 by Reactive Oxygen Species
AU - Ventre, Simona
AU - Indrieri, Alessia
AU - Fracassi, Chiara
AU - Franco, Brunella
AU - Conte, Ivan
AU - Cardone, Luca
AU - Di Bernardo, Diego
PY - 2015/5/22
Y1 - 2015/5/22
N2 - 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.
AB - 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.
KW - hairy and enhancer of split (Hes)
KW - human genetic mitochondrial diseases
KW - ltradian clock
KW - omitogenesis
KW - reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=84937759186&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937759186&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2015.03.007
DO - 10.1016/j.jmb.2015.03.007
M3 - Article
C2 - 25796437
AN - SCOPUS:84937759186
VL - 427
SP - 1887
EP - 1902
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 10
ER -