Caenorhabditis elegans (C. elegans) displays two sleep states- following cellular stress (SIS) and during development (DTS) - whose mechanisms appear to be at least partially distinct (Trojanowski et al, Journal of Neuroscience 2015; Turek et al, Curr. Biol. 2013; Hill et al, Curr. Biol. 2014). It also displays quiescent behavior under conditions of satiety (You et al, Cell Metab. 2008). Following exposure to conditions that cause cellular stress, epidermal growth factor (EGF) activates the ALA interneuron (Hill et al, Curr. Biol. 2014). KIN-29, a serine/threonine kinase, has been previously described to be involved in the regulation of both satiety quiescence (Van der Linden et al, Genetics 2008) and developmentally timed sleep in C. elegans (Funato et al, Nature 2016). In mice and Drosophila, a gain of function mutation in
kin-29 homologues, leads to an increased need for sleep (Funato et al, Nature 2016). To get at the mechanism by which SIK3/KIN-29 promotes sleep, we here study the role of
kin-29 in the regulation of developmentally timed sleep (DTS) and stress induced sleep (SIS) in C. elegans. Animals with a
kin-29 null mutation display defects in both DTS and SIS. Our preliminary data suggests that
kin-29's effect on sleep is mediated by the histone deacetylase HDA-4, since an
hda-4 mutation suppresses the defect in SIS and DTS seen in
kin-29 mutants.
kin-29 mutants display normal quiescence following EGF over-expression, suggesting that KIN-29 acts upstream of ALA activation in the SIS pathway. We are currently trying to identify the cells in which
kin-29 is acting to regulate sleep. To determine if KIN-29 activity is sufficient to induce sleep in C. elegans, as previously shown in mice and Drosophila, we are making transgenic animals with a
kin-29 PKA site mutated to make KIN-29 constitutively active. Finally, to understand when KIN-29 signaling is necessary we will use a conditional CRISPR/Cas9 system to knock out KIN-29 in animals following development. These studies aim to elucidate the conserved role of KIN-29/SIK3 in the regulation of sleep.