Epidermal growth factor signaling induces behavioral quiescence in Caenorhabditis elegans

Abstract

The epidermal growth factor receptor (EGFR)/ErbB receptor tyrosine kinases regulate several aspects of development, including the development of the mammalian nervous system. ErbB signaling also has physiological effects on neuronal function, with influences on synaptic plasticity and daily cycles of activity. However, little is known about the effectors of EGFR activation in neurons. Here we show that EGF signaling has a nondevelopmental effect on behavior in Caenorhabditis elegans. Ectopic expression of the EGF-like ligand LIN-3 at any stage induces a reversible cessation of feeding and locomotion. These effects are mediated by neuronal EGFR (also called LET-23) and phospholipase C-gamma (PLC-gamma), diacylglycerol-binding proteins, and regulators of synaptic vesicle release. Activation of EGFR within a single neuron, ALA, is sufficient to induce a quiescent state. This pathway modulates the cessation of pharyngeal pumping and locomotion that normally occurs during the lethargus period that precedes larval molting. Our results reveal an evolutionarily conserved role for EGF signaling in the regulation of behavioral quiescence.

Sleep and Development in Genetically Tractable Model Organisms

“…The C. elegans homolog of the circadian clock protein Period is required for clocking larval development and thus the timing of lethargus-its messenger RNA (mRNA) levels track the molting cycle (Jeon et al 1999;Tennessen et al 2006;Monsalve et al 2011). Multiple additional conserved signaling pathways exhibit functional similarities in mammalian, insect, and nematode sleep, including epidermal growth factor signaling, protein kinase A (PKA) and G (PKG) activity, dopamine signaling, and pigment dispersing factor (PDF) signaling (Graves et al 2003;Kramer et al 2003;Snodgrass-Belt et al 2005;Van Buskirk and Sternberg 2007;Foltenyi et al 2007;Raizen et al 2008;Langmesser et al 2009;Choi et al 2013Choi et al , 2015Iwanir et al 2013;Singh et al 2014).…”

“…Overexpression of EGFR ligands in worms and flies induces sleep-like behaviors (Foltenyi et al 2007;Van Buskirk and Sternberg 2007;Raizen et al 2008), and this behavioral state change acts through EGFR in both animals. The initial description of nematode sleep onset as molt specific was influential in the examination of a role for ecdysone-the major Drosophila steroid hormone-in fly sleep (Ishimoto and Kitamoto 2010).…”

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

“…C. elegans ($300 neurons) has a quiescent behavioral state during a period called lethargus. [260][261][262] It occurs before each of the four molts and exhibits some aspects of sleep, including higher arousal thresholds and a homeostatic response to mechanical stimulation during lethargus (specifically, an augmented quiescence after stimulation). 260 The periods of lethargus involve alterations of the worm's nervous system, suggesting that lethargus evolved to accommodate specific requirements of such alterations.…”

“…[260][261][262][263][264] The FG hypothesis predicts higher levels of specific protease-generated protein fragments in some or most C. elegans neurons (and possibly in other cell types as well) shortly before lethargus. If the FG hypothesis proves relevant to the causation and function of sleep in mammals, the resulting understanding could be ''turned around'' by asking whether the lethargus in C. elegans involves the generation and degradation of specific fragments and the remodeling of protein complexes after fragments' removal, and whether these processes are the molecular cause of lethargus.…”

Le ver endormi ?

“…L'ensemble de ces observations comportementales permettent d'établir une analogie entre la léthar-gie du nématode et le sommeil des mammifères. [9] révèle que l'activation de la voie EGF (epidermal growth factor) déclenche un état de léthargie chez le nématode. La surexpression de LIN-3, le seul facteur de croissance de type EGF présent chez C. elegans, induit un comportement de type léthargique.…”