A Conserved GEF for Rho-Family GTPases Acts in an EGF Signaling Pathway to Promote Sleep-like Quiescence inCaenorhabditis elegans

Abstract

Sleep is evolutionarily conserved and required for organism homeostasis and survival. Despite this importance, the molecular and cellular mechanisms underlying sleep are not well understood. Caenorhabditis elegans exhibits sleep-like behavioral quiescence and thus provides a valuable, simple model system for the study of cellular and molecular regulators of this process. In C. elegans, epidermal growth factor receptor (EGFR) signaling is required in the neurosecretory neuron ALA to promote sleep-like behavioral quiescence after cellular stress. We describe a novel role for VAV-1, a conserved guanine nucleotide exchange factor (GEF) for Rho-family GTPases, in regulation of sleep-like behavioral quiescence. VAV-1, in a GEF-dependent manner, acts in ALA to suppress locomotion and feeding during sleep-like behavioral quiescence in response to cellular stress. Additionally, VAV-1 activity is required for EGF-induced sleep-like quiescence and normal levels of EGFR and secretory dense core vesicles in ALA. Importantly, the role of VAV-1 in promoting cellular stress-induced behavioral quiescence is vital for organism health because VAV-1 is required for normal survival after cellular stress.KEYWORDS behavioral quiescence; Caenorhabditis elegans; sleep; Vav D ESPITE being a subject of formal study for over 150 years, sleep is not clearly understood. Moreover, various explanations for the functional role of sleep have been proposed, such as allowing "recharging" of cells following high metabolic activity (Benington and Heller 1995;Tu and McKnight 2006;Scharf et al. 2008) and remodeling of synapses built during wakefulness (Tononi and Cirelli 2006). Yet sleep problems have a significant impact on human health and are a leading reason for seeking medical attention (Mahowald and Schenck 2005). Therefore, there is a great need for understanding the cellular and molecular mechanisms that regulate sleep-wake cycles.Simple model organisms such as Caenorhabditis elegans have the potential to provide valuable information regarding sleep regulation. C. elegans is known for its easily manipulated genetics, small nervous system with mapped neuronal connectivity, stereotypical behaviors, and the ability to be studied efficiently in large numbers. Numerous studies have shown that C. elegans lethargus, a restful period that occurs before each molt of the cuticle during larval development, is neuronally regulated and likely orthologous to sleep in mammals (Van Buskirk and Sternberg 2007;Raizen et al. 2008;Van Buskirk and Sternberg 2010;Choi et al. 2013;Iwanir et al. 2013;Turek et al. 2013;Cho and Sternberg 2014;Singh et al. 2014). Lethargus quiescence in C. elegans shares several characteristics with mammalian sleep: inactivity (decreased locomotion and cessation of pharyngeal pumping, or feeding), a specific posture, reduced response to aversive stimuli, and rapid reversibility (Cassada and Russell 1975;Raizen et al. 2008;Schwarz et al. 2012;Iwanir et al. 2013;Cho and Sternberg 2014). In addition, lethargus quiescence is under ...

Acute Sleep Deprivation Blocks Short- and Long-Term Operant Memory inAplysia

“…Sleep, through discrete mechanisms, occurs either developmentally during the quiescent periods between larval stages or following the induction of cellular stress with the amount of sleep correlated to the degree of the stressful stimulus. 22,[77][78][79][80] Thus, the timing of developmental sleep and the stress-induced sleep during adulthood in C. elegans make it more difficult to study the interactions of sleep with memory. To determine the persistence of sleep deprivation on shortterm memory, animals were sleep deprived for 9 h and allowed to recover for 24 or 48 h prior to learning that food is inedible (LFI) training.…”

Stress-Induced Sleep After Exposure to Ultraviolet Light Is Promoted by p53 inCaenorhabditis elegans

“…The function of sleep as a restorative state has also been demonstrated in both mammals and nematodes. After a heat shock, worms that cannot sleep have reduced survival (Hill et al 2014;Fry et al 2016). Similarly, in rabbits, animals that sleep more after an infection are more likely to survive than rabbits that sleep less (Toth et al 1993;Imeri and Opp 2009).…”

A mechanism for sickness sleep: lessons from invertebrates

“…A similar experiment was carried out in animals with defective ALA function due to a mutation in the guanine nucleotide‐exchange factor VAV‐1, which is expressed in and functions in ALA. vav‐1 mutant animals, like ALA‐less animals, show reduced survival after heat shock exposure (Fry et al . ). Therefore, in C. elegans , sleep after cellular stress is beneficial to survival.…”