Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling

Creators: Lee, Daniel A.; Liu, Justin; Hong, Young; Lane, Jacqueline M.; Hill, Andrew J.; Hou, Sarah L.; Wang, Heming; Oikonomou, Grigorios; Pham, Uyen; Engle, Jae; Saxena, Richa; Prober, David A.

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.

Additional Information

© 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). Submitted 21 March 2019; Accepted 17 September 2019; Published 13 November 2019. We thank members of the Prober Lab, P. Sternberg, R. Nath, H. Wang, C. Oikonomou, and J. Bedont for feedback. We also thank H. S. Dashti, C. Singh, D. Chilin, V. Sapin, T. Cammidge, H. Hurley, and C. Cook for technical assistance. Funding: This work was supported by grants from the National Institutes of Health (NIH) (D.A.L.: K99NS097683 and F32NS084769; G.O.: F32NS082010; D.A.P.: R01NS070911 and R01NS101158; J.M.L.: T32HL007567; R.S.: R01DK107859, R01HL113338, R01DK102696, and R01DK105072) and the Mallinckrodt (to D.A.P.), Rita Allen (to D.A.P.), and Brain and Behavior Research (to D.A.P. and D.A.L.) foundations. The GTEx Project was supported by the Common Fund of the Office of the Director of the NIH and by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Author contributions: D.A.L., J.L., and D.A.P. conceived the project and designed the experiments. D.A.L. performed most of the experiments and analyzed the data, with assistance from J.L., Y.H., A.J.H., S.L.H., G.O., U.P., J.E. and D.A.P. J.M.L., H.W., and R.S. performed the sleep genetic association analysis. D.A.L. and D.A.P. wrote the manuscript with input from J.M.L. and R.S. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors. Custom PERL and MATLAB code used for zebrafish behavioral analysis is available upon request and posted online (35). Human sleep genetic association analysis was conducted using the U.K. Biobank Resource under application number 6818.

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