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1 General Description

Dauer development is regulated by neuroendocrine pathways sensing environmental signals of poor growth conditions, such as population overcrowding, limited food supply or high temperature. Population density is determined by the level of constitutively-secreted dauer pheromone (Golden and Riddle, 1984). When population density rises, environmental pheromone levels increase, triggering L1 larvae to enter the dauer pathway (DNeuroRegFIG 1). The presence of food suppresses pheromone’s dauer-inducing activity and also induces dauer recovery (Golden and Riddle, 1984). Elevated temperature (>25°C) can enhance dauer formation, possibly by stimulating pheromone production or altering neuronal signaling in response to pheromone (Ailion and Thomas, 1999; Ailion and Thomas, 2003; Mahoney et al., 2006; Joo et al., 2010). Dauer pheromones have been isolated and belong to a group of lipid molecules called ascarosides (Golden and Riddle, 1982; Ludewig and Schroeder, 2013). In contrast, less is known about the chemical identity of the food signal at this time.

DNeuroRegFIG 1: Environmental conditions control larval commitment to dauer development
DNeuroRegFIG 1: Environmental conditions control larval commitment to dauer development. Food and pheromone signals, which antagonistically regulate dauer entry, are detected by chemosensory amphidial neurons. Pheromone is constitutively secreted and accumulates in the environment as an indicator of population density. In the upper panel, plentiful food and scarce pheromone indicate an environment suitable for reproduction. Under these conditions, larvae bypass dauer arrest and become fertile adults. In the lower panel, scarce food and abundant pheromone reflect harsh environmental conditions. Under these conditions, L1 larvae commit to dauer arrest to await conditions that are more hospitable for reproduction.

2 Dauer Pheromone

Endogenous dauer-inducing pheromone consists of a mixture of ascarosides, which are derivatives of the dideoxy-sugar, ascarylose (DNeuroRegFIG 2) (Jeong et al. 2005; Butcher et al., 2007, 2008). Ascaroside derivatives are widely produced by members of the nematode clade, where they may function as a conserved mechanism for social and developmental signaling (Braendle, 2012; Choe et al., 2012a). In the insect parasitic nematode, Heterorhabditis bacteriophora, ascaroside derivatives regulate the developmental switch to the infective form (Noguez et al., 2012). Many ascarosides are sex-specific attractants, responsible for luring mating partners of the opposite sex, as shown for the obligate male/female species Panagrellus redivivus (Choe et al., 2012b).

DNeuroRegFIG 2: Dominant ascarosides detected in C. elegans dauer-inducing pheromones.
DNeuroRegFIG 2: Dominant ascarosides detected in C. elegans dauer-inducing pheromones. Adapted with permission from von Reuss et al., 2012.

Several different dauer-inducing ascarosides have been isolated from C. elegans extracts. Chemically-synthesized versions of these ascarosides promote dauer arrest. The most potent and abundant ascaroside is ascr#5, also known as C3 ascaroside, followed by ascr#2 (C6) and ascr#3 (C9) (Butcher et al., 2007, 2008). Additional ascarosides are also present as minor components in extracts, including ascr#1 (daumone, C7) (Jeong et al., 2005; Butcher et al., 2007, 2008). Synthetic versions of these derivatives are capable of regulating dauer formation, with ascr#5 (C3) displaying the most potent activity (Butcher et al., 2008). Ascarosides that are more highly saturated and more polar tend to be retained in the body, while less-polar or unsaturated derivatives are more effectively excreted (von Reuss et al., 2012).

Ascaroside biosynthesis is dependent upon multiple biochemical pathways, including those for peroxisomal fatty-acid elongation and beta-oxidation (Butcher et al., 2009; Joo et al., 2010; von Reuss et al., 2012). The pathways that carry out pheromone synthesis are essential for C. elegans viability. For example, mutants defective in peroxisomal fatty acid oxidation exhibit developmental delays, have shortened adult lifespan and accumulate intestinal fat deposits (Joo et al., 2009; 2010). Ascaroside production is stimulated at higher temperature, paralleling the increase in dauer larvae formation seen at this temperature (Golden and Riddle, 1984; Joo et al., 2010; Ailion and Thomas, 1999, 2003; Mahoney et al., 2006). Expression and tissue-specific rescue experiments point to the intestine as the most significant source of ascaroside production and excretion, although some pheromone synthetic enzymes are also expressed in other tissues, including hypodermis and muscle (Butcher et al., 2009).

3 Neuronal Pathways Regulating Dauer Arrest

The dauer-inducing ascarosides act on amphid neurons that contact the environment at the distal openings of the amphid channels. Mutations causing amphid channel blockade impair pheromone signaling and prevent dauer arrest in response to pheromone (Albert et al., 1981). daf-7 encodes a TGF-beta ligand expressed in amphids that is critical for promoting reproductive development. daf-7 expression in ASI prevents dauer arrest and promotes development into fertile adults. Pheromone repressed the expression of daf-7::GFP reporters in ASI (Ren et al., 1996; Schackwitz et al., 1996; Peckol et al., 2001; Nolan, et al., 2002). Furthermore, ablation of ASI, together with ADF, ASG and ASJ, causes inappropriate dauer arrest under replete conditions (Bargmann and Horvitz, 1991; Schackwitz et al., 1996). Thus, pheromone directs dauer formation by repressing daf-7 pathway signaling in amphids.

In the amphids, ascarosides signal via 7-transmembrane domain receptors coupled to G-protein signaling pathways. The receptors and signaling partners for C. elegans ascarosides appear to be ascaroside- and neuron-specific. In particular, ascr#2 (C6) and ascr#5 (C3) act on ASI through different receptors. In ASI, ascr#2 (C6) binds to DAF-37/GPCR, possibly in a heterodimeric complex with DAF-38, to directly repress daf-7 expression and promote dauer formation (Park et al., 2012). In contrast, ascr#5 (C3) binds to SRG-36/-37 heterodimeric receptors in ASI (McGrath et al., 2011).

Amphid signaling can affect dauer formation in other ways, as well. ASK activity seems to be required for larvae to enter the dauer stage, as ASK ablation can prevent dauer entry in the presence of pheromone (Schackwitz et al., 1996; Kim et al., 2009).  In ASK neurons, ascr#2 (C6) signaling is mediated by the SRBC-64/-66 receptor, coupled to GPA-3/G-alpha, to inhibit DAF-11/guanylyl cyclase (Kim et al., 2009). It is thought that ASK controls dauer formation indirectly by acting on ASI through as yet undefined pathways (Kim et al., 2009). Finally, ASJ has been shown by ablation and exogenous activation experiments to promote dauer recovery (Bargmann and Horvitz, 1991; Schultheis et al., 2011). Since the food signal also promotes dauer recovery, ASJ may represent the site of action for this pathway (Golden and Riddle, 1984).

An insulin-like signaling pathway collaborates with the daf-7/TGF-beta pathway to regulate dauer formation (Morris et al., 1996; Kimura et al., 1997). The C. elegans genome encodes 40 insulin-like peptides (ILP), which are potential ligands for the DAF-2/insulin-receptor like protein (Pierce et al., 2001). ILPs are expressed throughout the body, including in neurons and the intestine. One neuronal ILP, DAF-28, expressed in ASI and ASJ, can antagonize dauer formation, suggesting it may transduce environmental dauer-inducing signals (Li et al., 2003). However, other ILPs impact daf-2 pathway activity from non-neuronal tissues, such as the intestine (Murphy et al., 2007).  

Specialized endocrine cells in the head, named XXX cells (see Atypical Epithelial Cells), also regulate the dauer decision through synthesis of dafachronic acid (DA), the ligand for the DAF-12/nuclear hormone receptor (Gerisch et al., 2001; Jia et al., 2002). In L1 larvae, DA synthesis by the XXX cells reflects the presence or absence of environmental cues for dauer arrest, such as pheromone, food and temperature. In L1 larvae, favorable environmental conditions stimulate DA synthesis by the XXX cells, allowing larvae to bypass dauer. In later larval stages, the hypodermis becomes a second site for DA synthesis, propelling development into fertile adulthood (Schaedel et al., 2012). In unfavorable environments, DA synthesis by the XXX cells is reduced, committing larvae to enter dauer arrest (Schaedel et al., 2012). Components of the DAF-2/insulin-like pathway are also expressed in XXX cells, where they may modulate DA synthesis in response to environmental factors (Ohkura et al., 2003; Hu et al, 2006).

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Edited for the web by Laura A. Herndon. Last revision: March 18, 2013. This chapter should be cited as: Wolkow, C.A. and Hall, D.H. 2013. Nervous system regulation of dauer diapause. In WormAtlas. doi:10.3908/wormatlas.3.5

We would like to thank David Gems for his suggestions for this section.