The genetics of dauer arrest were first revealed with the identification of daf mutants in which dauer formation is misregulated (Riddle et al., 1981). Some daf mutants display the dauer-constitutive (Daf-c) phenotype, forming dauers inappropriately regardless of environmental conditions (Riddle et al., 1981). These animals carry mutations either in the daf-2/insulin-like pathway or the daf-7/TGF-ß pathway regulating dauer arrest (Thomas et al., 1993; Gottleib and Ruvkun, 1994; Hu, 2007). The daf-2 and daf-7 pathways regulate parallel, and independent, inputs into the dauer decision (DGenFIG 1). Mutations inactivating the ligands, receptors or downstream signals for these pathways cause dauer arrest, even in favorable environments. A second group of mutants was also identified that fail to form dauers when combined with specific Daf-c mutants. These dauer-defective (Daf-d) mutants carry mutations in genes that function to antagonize signaling by the daf-2/insulin-like or daf-7/TGF-ß pathways. This research revealed that insulin-like and TGF-ß signaling pathways can function to link environmental conditions to developmental events.

2 Pheromone and Nutrient Sensing Pathways

High population density triggers entry into the dauer program through elevated levels of a constitutively-secreted pheromone (Golden and Riddle, 1982). Dauer pheromone is a mixture of ascarosides, lipid-modified versions ascarylose sugars (Jeong et al., 2005; Butcher et al., 2007; DNeuroRegFIG 2). Ascarosides signal through G-protein coupled receptors in the ciliated neurons on the head (Kim et al., 2009; McGrath et al., 2011; Park et al., 2012; DNeuroFIG 3). Pheromone-regulated G-protein signaling may ultimately regulate expression of the DAF-7/TGFß ligand, whose expression is antagonized by pheromone (Schackwitz et al., 1996; Ren et al., 1998). Larvae lacking functional ciliated neurons are resistant to the effects of dauer pheromone and bypass dauer arrest even under very crowded conditions (Albert et al., 1981; Bargmann and Horvitz, 1991; Vowels and Thomas, 1992). The DAF-7/TGF-ß ligand is expressed in the ASI head neurons and is regulated by pheromone levels (Schackwitz et al., 1996; Ren et al., 1998). Pheromone induction of dauer arrest is enhanced when food levels are low (See DNeuroRegFIG 1). Food and nutrient signals may be transduced via the multitude of insulin/IGF-I-like peptides encoded in the C. elegans genome which are potential ligands for the DAF-2/insulin receptor-like protein (Pierce et al., 2001; Li et al., 2003; Cornils et al., 2011). (See also Dauer Nervous System - Regulation of Diapause.)

Both the daf-2/insulin-like and daf-7/TGF-ß pathways converge to regulate the activity of a nuclear hormone receptor (NHR) encoded by the daf-12 gene (Antebi et al., 2000). Defects in daf-12 activity disrupt the timing of developmental events that occur in the third larval stage, such as gonad leader cell migration and L3 seam cell divisions (Antebi et al., 1998). The daf-12 gene also has complex effects on dauer arrest, as certain daf-12 mutations cause constitutive dauer arrest while others prevent dauer formation.

The DAF-12 NHR is regulated by a steroid ligand called dafachronic acid, which is produced by a biosynthetic pathway involving several body tissues (Gerisch et al., 2001; Jia et al., 2002; Mak and Ruvkun, 2004; Motola et al., 2006). Dafachronic acid biosynthesis is regulated by an autonomic feedback loop to maintain adequate levels of this pro-development hormone (Rottiers et al., 2006; Schaedel et al., 2012). Signals from environments suitable for proliferation, such as high levels of DAF-2/insulin receptor or DAF-7/TGF-ß signaling, may stimulate dafachronic acid synthesis, providing plentiful ligand for DAF-12/NHR binding (Gerisch et al., 2001; Jia et al., 2002; Mak and Ruvkun, 2004). The liganded form of DAF-12/NHR promotes reproductive development and proliferation in these environments. Conditions that disrupt dafachronic acid, such as scarce food or overcrowding, would leave DAF-12/NHR in the unliganded form, committing larvae to arrest development as dauers. (See also Dauer Nervous System - Regulation of Diapause.)

4 References

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