NERVOUS SYSTEM REGULATION OF DAUER DIAPAUSE
Click image for closeup view Click pictures for new window with figure and legend, click again for high resolution image

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).



4 References

Ailion, M., Inoue, T., Weaver, C.I., Holdcraft, R.W. and Thomas, J.H. 1999. Neurosecretory control of aging in Caenorhabditis elegans. Proc. Natl. Acad. Sci. 96: 7394-7397. Article

Ailion, M. and Thomas, J.H. 2003. Isolation and characterization of high-temperature-induced Dauer formation mutants in Caenorhabditis elegans. Genetics 165:127-144. Article

Albert, P.S., Brown, S.J. and Riddle, D.L. 1981. Sensory control of dauer larva formation in Caenorhabditis elegans. J. Comp. Neurol. 198: 435-451. Abstract

Bargmann, C.I. and Horvitz, H.R. 1991. Control of larval development by chemosensory neurons in Caenorhabditis elegans. Science 251: 1243-1246. Abstract

Braendle, C. 2012. Pheromones: Evolving language of chemical communication in nematodes. Curr. Biol. 22: R294-R296. Abstract

Butcher, R.A., Fujita, M., Schroeder, F.C. and Clardy, J. 2007. Small-molecule pheromones that control development in Caenorhabditis elegans. Nat. Chem. Biol. 3: 420-422. Abstract

Butcher, R.A., Ragains, J.R., Kim, E. and Clardy, J. 2008. A potent dauer pheromone component in Caenorhabditis elegans that acts synergistically with other components. Proc. Natl. Acad. Sci. 105: 14288-14292. Article

Butcher, R.A., Ragains, J.R., Li, W., Ruvkun, G., Clardy, J. and Mac, H.Y. 2009. Biosynthesis of the Caenorhabditis elegans dauer pheromone. Proc. Natl. Acad. Sci. 106: 1875-1879. Article

Choe, A., von Reuss, S.H., Kogan, D., Gasser, R.B., Platzer, E.G., Schroeder, F.C. and Sternberg, P. 2012a. Ascaroside signaling is widely conserved among nematodes. Curr. Biol. 22: 772-780. Abstract

Choe, A., Chuman, T., von Reuss, S.H., Dossey, A.T., Yim, J.J., Ajredini, R., Kolawa, A.A., Kaplan, F., Alborn, H.T., Teal, P.E.A., Schroeder, F.C., Sternberg, P.W. and Edison, A.S. 2012b. Sex-specific mating pheromones in the nematode Panagrellus redivivus. Proc. Natl. Acad. Sci. 109: 20949-20954. Abstract

Gerisch, B., Weitzel, C., Kober-Eisermann, C., Rottiers, V. and Antebi, A. 2001. A hormonal signaling pathway influencing C. elegans metabolism, reproductive development, and life span. Dev. Cell. 1: 841-851. Article

Golden, J.W. and Riddle, D.L. 1982. A pheromone influences larval development in the nematode Caenorhabditis elegans. Science. 218: 578-580. Abstract

Golden, J.W. and Riddle, D.L. 1984. Caenorhabditis elegans dauer larva: Developmental effects of pheromone, food and temperature. Dev. Biol. 102: 368-378. Abstract

Hu, P.J., Xu, J. and Ruvkun, G. 2006. Two membrane-associated tyrosine phosphatase homologs potentiate C. elegans AKT-1/PKB signaling. PLoS Genet. 2: e99. Article

Jeong, P.-Y., Jung, M., Yim, Y.-H., Kim, H., Park, M., Hong, E., Lee, W., Kim, Y.H., Kim, K. and Paik, Y.-K. 2005. Chemical structure and biological activity of the Caenorhabditis elegans dauer-inducing pheromone. Nature 433: 541-545. Abstract

Jia, K., Albert, P.S. and Riddle, D.L. 2002. DAF-9, a cytochrome P450 regulating C. elegans larval development and adult longevity. Development 129: 221-231. Article

Joo, H.-J., Yim, Y.-H., Jeong, P.-Y., Jin, Y.-X., Lee, J.-E., Kim, H., Jeong, S.-K., Chitwood, D.J. and Paik, Y.-K. 2009. Caenorhabditis elegans utilizes dauer pheromone biosynthesis to dispose of toxic peroxisomal fatty acids for cellular homeostasis. Biochem. J. 422: 61-71. Article

Joo, H.-J., Kim, K.-Y., Yim, Y.-H., Jin, Y.-X., Kim, H., Kim, M.-Y. and Paik, Y.-K. 2010. Contribution of the peroxisomal acox gene to the dynamic balance of daumone production in Caenorhabditis elegans. J. Biol. Chem. 285: 29319-29325. Article

Kim, K., Sato, K., Shibuya, M., Zeiger, D.M., Butcher, R.A., Ragains, J.R., Clardy, J., Touhara, K., and Sengupta, P. 2009. Two chemoreceptors mediate developmental effects of dauer pheromone in C. elegans. Science 326: 994-998. Abstract

Kimura, K.D., Tissenbaum, H.A., Liu, Y., and Ruvkun, G. 1997. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277: 942-946. Abstract

Li, W., Kennedy, S.G. and Ruvkun, G. 2003. daf-28 encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway. Genes Dev. 17: 844-858. Article

Ludewig, A.H. and Schroeder, F.C. 2013. Ascaroside signaling in C. elegans. In WormBook (ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.155.1) Article

Mahoney, T.R., Liu, Q., Itoh, T., Luo, S., Hadwiger, G., Vincent, R., Wang, Z-W., Fukuda, M. and Nonet, M.L. 2006. Regulation of synaptic transmission by RAB-3 and RAB-27 in Caenorhabditis elegans. Mol. Biol. Cell 17: 2617-2625. Article

McGrath, P.T., Xu, Y., Ailion, M., Garrison, J.L., Butcher, R.A. and Bargmann, C.I. 2011. Parallel evolution of domesticated Caenorhabditis species targets pheromone receptor genes. Nature 477: 321-325. Abstract

Morris, J.Z., Tissenbaum, H.A., and Ruvkun, G. 1997. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382: 536-539. Abstract

Murphy, C.T., Lee, S.-J. and Kenyon, C. 2007. Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans. Proc. Natl. Acad. Sci. 104: 19046-50. Article

Noguez, J.H., Conner, E.S., Zhou, Y., Ciche, T.A., Ragains, J.R. and Butcher, R.A. 2012. A novel ascaroside controls the parasitic life cycle of the entomopathogenic nematode Heterorhabditis bacteriophora. ACS Chem. Biol. 7: 961-966. Abstract

Nolan, K.M., Sarafi-Reinach, T.R., Horne, J.G., Saffer, A.M. and Sengupta, P. 2002. The DAF-7 TGF-beta signaling pathway regulates chemosensory receptor gene expression in C. elegans. Genes Dev. 16: 3061-73. Article

Ohkura, K., Suzuki, N., Ishihara, T. and Katsura, I. 2003. SDF-9, a protein tyrosine phosphatase-like molecule, regulates the L3/dauer developmental decision through hormonal signaling in C. elegans. Development 14: 3237-3248. Article

Park, D., O’Doherty, I., Somvanshi, R.K., Bethke, A., Schroeder, F.C., Kumar, U. and Riddle, D.L. 2012. Interaction of structure-specific and promiscuous G-protein-coupled receptors mediates small-molecule signaling in Caenorhabditis elegans. Proc. Natl. Acad. Sci. 109: 9917-9922. Abstract

Peckol, E.L, Troemel, E.R. and Bargmann, C.I. 2001. Sensory experience and sensory activity regulate chemosensory receptor gene expression in Caenorhabditis elegans. Proc. Natl. Acad. Sci. 98: 11032-11038. Article

Pierce, S.B., Costa, M., WIsotzkey, R., Devadhar, S., Homburger, S.A., Buchman, A.R., Ferguson, K.C., Heller, J., Platt, D.M., Pasquinelli, A.A., Liu, L.X., Doberstein, S.K. and Ruvkun, G. 2001. Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev. 15: 672-86. Article

Ren, P., Lim, C.S., Johnsen, R., Albert, P.S., Pilgrim, D, and Riddle, D.L. 1996. Control of C. elegans larval development by neuronal expression of a TGF-β homolog. Science 274: 1389-1391. Abstract

Schackwitz, W.S., Inoue, T. and Thomas, J.H. 1996. Chemosensory neurons function in parallel to mediate a pheromone response in C. elegans. Neuron 17: 719-728. Article

Schaedel, O.N., Gerisch, B., Antebi, A. and Sternberg, P.W. 2012. Hormonal signal amplification mediates environmental conditions during development and controls an irreversible commitment to adulthood. PLoS Biol. 10: e1001306. Article

Schultheis, C., Liewald, J.F., Bamberg, E., Nagel, G. and Gottschalk, A. 2011. Optogenetic long-term manipulation of behavior and animal development. PLoS ONE. 6: e18766. Article

von Reuss, S.H., Bose, N., Srinivasan, J., Yim, J.J., Judkins, J.C., Sternberg, P.W. and Schroeder, F.C. 2012. Comparative metabolomics reveals biogenesis of ascarosides, a modular library of small-molecule signals in C. elegans. J. Am. Chem. Soc. 134: 1817-1824. Article



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.

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

image
 
image