Barlow, I; (2017) Dreammist: a highly conserved novel peptide implicated in zebrafish sleep. Doctoral thesis , UCL (University College London).

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Abstract

Genetic and neuronal regulation of sleep is highly conserved from zebrafish to humans. However, our understanding of the molecular and neurobiological mechanisms that regulate sleep onset, length, and function remain relatively limited. A high-throughput locomotor tracking system to monitor zebrafish larvae sleep has identified a novel gene, dreammist (dmist), implicated in regulating vertebrate sleep. Homozygous viral disruption to dmist significantly decreases total sleep during the day compared to wild type siblings. Computationally predicted to encode a small (<70aa) transmembrane peptide, dmist gene structure and synteny is highly conserved among vertebrates, including fish, birds, mice, and humans. Furthermore, in situ hybridisation in zebrafish embryos shows localised expression of dmist from 1 day post fertilisation (1dpf) in the eye, ventral telencephalon, diencephalon, and hindbrain, with expression becoming more widespread in the brain at later stages of development (5dpf). In vivo validation of Dmist subcellular localisation in early zebrafish embryos indicates that Dmist may be dynamically processed during early stages of development with localisation in the membrane, but also the nucleus. Moreover, a split-ubiquitin yeast two-hybrid screen to find Dmist-interacting partners identified several candidate transmembrane proteins implicated in hearing, photoreception, and neurite outgrowth. To further understand Dmist’s role in regulating sleep, detailed behavioural analysis of CRISPR- generated targeted knock-out animals indicates that dmist mutants have a functioning visual system, but sensitivity to ambient light may affect their sleep and activity. Therefore, through investigating Dmist’s function and role at the cellular, neuroanatomical, and behavioural level in wild-type and mutant zebrafish larvae this work has contributed to our understanding of the function of a highly conserved, novel, and previously unannotated gene in regulating sleep and wake, and possibly other biological processes.

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