Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling
Open Access
- 1 November 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 5 (11), eaax4249
- https://doi.org/10.1126/sciadv.aax4249
Abstract
The genetic bases for most human sleep disorders and for variation in human sleep quantity and quality are largely unknown. Using the zebrafish, a diurnal vertebrate, to investigate the genetic regulation of sleep, we found that epidermal growth factor receptor (EGFR) signaling is necessary and sufficient for normal sleep levels and is required for the normal homeostatic response to sleep deprivation. We observed that EGFR signaling promotes sleep via mitogen-activated protein kinase/extracellular signal–regulated kinase and RFamide neuropeptide signaling and that it regulates RFamide neuropeptide expression and neuronal activity. Consistent with these findings, analysis of a large cohort of human genetic data from participants of European ancestry revealed that common variants in genes within the EGFR signaling pathway are associated with variation in human sleep quantity and quality. These results indicate that EGFR signaling and its downstream pathways play a central and ancient role in regulating sleep and provide new therapeutic targets for sleep disorders.Funding Information
- National Heart, Lung, and Blood Institute (T32HL007567)
- National Heart, Lung, and Blood Institute (R01HL113338)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107859)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102696)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK105072)
- National Institute of Neurological Disorders and Stroke (R01NS101158)
- Brain and Behavior Research Foundation
- Rita Allen Foundation
- Edward Mallinckrodt, Jr. Foundation
- National Institute of Neurological Disorders and Stroke (R01NS095824)
- National Institute of Neurological Disorders and Stroke (R01NS101665)
- National Institute of Neurological Disorders and Stroke (R01NS070911)
- National Institute of Neurological Disorders and Stroke (K99NS097683)
- National Institute of Neurological Disorders and Stroke (F32NS084769)
- Brain and Behavior Research Foundation
- National Institute of Neurological Disorders and Stroke (F32NS082010)
This publication has 68 references indexed in Scilit:
- A large-scale in vivo analysis reveals that TALENs are significantly more mutagenic than ZFNs generated using context-dependent assemblyNucleic Acids Research, 2013
- LocusZoom: regional visualization of genome-wide association scan resultsBioinformatics, 2010
- Lineage-specific co-evolution of the Egf receptor/ligand signaling systemBMC Evolutionary Biology, 2010
- KSR2 Is an Essential Regulator of AMP Kinase, Energy Expenditure, and Insulin SensitivityCell Metabolism, 2009
- Use-Dependent Plasticity in Clock Neurons Regulates Sleep Need in DrosophilaScience, 2009
- Behavioral effects of systemic transforming growth factor-alpha in Syrian hamstersBehavioural Brain Research, 2009
- Viral 2A peptides allow expression of multiple proteins from a single ORF in transgenic zebrafish embryosgenesis, 2007
- Receptor tyrosine kinases: mechanisms of activation and signalingCurrent Opinion in Cell Biology, 2007
- Artery/Vein Specification Is Governed by Opposing Phosphatidylinositol-3 Kinase and MAP Kinase/ERK SignalingCurrent Biology, 2006
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001