A genetic screen identifies dreammist as a regulator of sleep

• Published in: bioRxiv
• Main Authors: Barlow, Ida L, Mackay, Eirinn, Wheater, Emily, Goel, Aimee, Lim, Sumi, Zimmerman, Steve, Woods, Ian, Prober, David A, Rihel, Jason
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 06.12.2020
• Subjects: CRISPR; Danio rerio; Genetic screening; Hyperactivity; Insertion; Movement disorders; Mutants; Na+/K+-exchanging ATPase; Neuromodulation; Phospholemman; Proteins; Sleep; Sleep and wakefulness
• DOI: 10.1101/2020.11.18.388736

Abstract Sleep is a nearly universal feature of animal behaviour, yet many of the molecular, genetic, and neuronal substrates that orchestrate sleep/wake transitions lie undiscovered. Employing a viral insertion sleep screen in larval zebrafish, we identified a novel mutant, dreammist (dmist), with altered sleep-wake dynamics. CRISPR/Cas9-mediated disruption of dmist also led to behavioural hyperactivity and reduced sleep at night. The neuronally expressed dmist gene is conserved across vertebrates and encodes a small single-pass transmembrane protein that is structurally similar to the Na+,K+-ATPase regulator, FXYD1/Phospholemman. Disruption of either fxyd1 or atp1a3a, a Na+,K+-ATPase alpha-3 subunit associated with several heritable movement disorders in humans, led to decreased night-time sleep. As intracellular Na+ concentration is disrupted in dmist mutant brains after high neuronal activity similarly to atp1a3a mutants, but is also elevated specifically at night, we propose that sleep-wake stability is modulated by Dmist-dependent changes to Na+ pump function during sleep homeostatic challenge and at specific times of the day-night cycle. Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵* Lead author: Jason Rihel j.rihel{at}ucl.ac.uk * Significance statement: Sleep is an essential component of behaviour, but the genes that regulate sleep and wake states are still being uncovered. A viral insertion screen in zebrafish identified a novel sleep mutant called dreammist, in which a small, highly-conserved transmembrane protein is disrupted. The discovery of dreammist highlights the importance of a class of small transmembrane-protein modulators of the sodium pump in setting appropriate sleep duration. * We have amended the acknowledgements to better reflect all contributions.