FMRFamide-like FLP-13 Neuropeptides Promote Quiescence following Heat Stress in Caenorhabditis elegans

Abstract

Summary Among the most important decisions an animal makes is whether to engage in active movement and feeding behavior or to become quiescent. The molecular signaling mechanisms underlying this decision remain largely unknown. The nematode Caenorhabditis elegans displays sleep-like quiescence following exposures that result in cellular stress [1]. The neurosecretory ALA neuron is required for this stress-induced recovery quiescence [1] but the mechanisms by which ALA induces quiescence have been unknown. We report here that quiescence induced by heat stress requires ALA depolarization and release of FMRFamide-like neuropeptides encoded by the flp-13 gene. Optogenetic activation of ALA reduces feeding and locomotion in a FLP-13-dependent manner. Over expression of flp-13 is sufficient to induce quiescent behavior during normally active periods. We have here identified a major biological role for FMRFamide-like neuropeptides in nematodes, and suggest that they may function in a similar capacity in other organisms.

Sleep and Development in Genetically Tractable Model Organisms

“…Cessation of locomotion and feeding can also be induced in adult C. elegans by satiety, stress, or genetic manipulations. Examples of the latter include heat-shock-induced activation of epidermal growth factor signaling (Van Buskirk and Sternberg 2007), mutations affecting cGMP, cAMP, or TGF-b signaling You et al 2008;Iwanir et al 2013), specific rescue of a peptidergic or insulin/insulin-like signaling pathway (Driver et al 2013;Hill et al 2014;Nagy et al 2014;Nelson et al 2014), or optogenetic activation of an avoidance response-promoting neuron (Cho and Sternberg 2014). Such findings potentially decouple worm sleep from molting.…”

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

“…Indeed, RIA and RIS neurons, for instance, are also involved in lethargus quiescence Turek et al 2013). Moreover, subsequent publications have shed light on perhaps a more vital role of ALA: induction of cellular stress-induced quiescence that is correlated with survival rates after cellular stress (e.g., noxious heat) Nelson et al 2014). Mutation of ceh-17, a transcription factor required for LET-23/EGFR and PLC-3/PLCg expression in ALA, and mutation of flp-13, a gene encoding FMRFamide-like neuropeptides expressed in ALA, both disrupt EGF-and cellular stress-induced quiescence.…”

“…Perhaps VAV-1 influences localization or release of FLP-13 (and/or other neuropeptides); further studies are needed to investigate these possibilities. Cellular stress induced by noxious heat causes perturbation of cellular homeostasis, which drives sleep-like behavioral quiescence Nelson et al 2014). The sleeplike behavioral quiescence induced by cellular stress results in an initial short-lived quiescent state (1 hr) followed by brief recovery and a second, prolonged quiescent state (several hours) .…”

“…In addition, lethargus quiescence is under homeostatic regulation (e.g., depriving animals in lethargus or rest by stimulation increases sleep drive), and prolonged deprivation of rest is lethal Driver et al 2013), as it is in rats (Rechtschaffen and Bergmann 2002). Recently, C. elegans has further been shown to display sleep-like quiescence following exposure to noxious stimuli that result in cellular stress Nelson et al 2014 Previously, we demonstrated that VAV-1, an evolutionarily conserved guanine nucleotide exchange factor (GEF) for Rho-family GTPases, is an important factor in a neural circuit that regulates C. elegans locomotion (Fry et al 2014). We found that VAV-1 is required in the ALA interneuron to reduce locomotory speed in active adult animals.…”

“…In addition, lethargus quiescence is under homeostatic regulation (e.g., depriving animals in lethargus or rest by stimulation increases sleep drive), and prolonged deprivation of rest is lethal Driver et al 2013), as it is in rats (Rechtschaffen and Bergmann 2002). Recently, C. elegans has further been shown to display sleep-like quiescence following exposure to noxious stimuli that result in cellular stress Nelson et al 2014). Fascinatingly, molecules that regulate behavioral quiescence in C. elegans and Drosophila are conserved and influence sleep in mammals, indicating evolutionarily conserved origins of sleep and the potential utility of studying sleep in such simple animals Sehgal and Mignot 2011;.…”