Comparative Metabolomics Reveals Biogenesis of Ascarosides, a Modular Library of Small-Molecule Signals in C. elegans

Self Cite

112

Animals find mates and food, and avoid predators, by navigating to regions within a favorable range of available sensory cues. How are these ranges set and recognized? Here we show that male Caenorhabditis elegans exhibit strong concentration preferences for sex-specific small molecule cues secreted by hermaphrodites, and that these preferences emerge from the collective dynamics of a single male-specific class of neurons, the cephalic sensory neurons (CEMs). Within a single worm, CEM responses are dissimilar, not determined by anatomical classification and can be excitatory or inhibitory. Response kinetics vary by concentration, suggesting a mechanism for establishing preferences. CEM responses are enhanced in the absence of synaptic transmission, and worms with only one intact CEM show nonpreferential attraction to all concentrations of ascaroside for which CEM is the primary sensor, suggesting that synaptic modulation of CEM responses is necessary for establishing preferences. A heterogeneous concentrationdependent sensory representation thus appears to allow a single neural class to set behavioral preferences and recognize ranges of sensory cues.T he chemical senses of taste and smell are an important source of sensory input for organisms from worms to humans, and elements of the olfactory system are evolutionarily conserved across metazoa (1, 2). The neural mechanisms of olfactory processing are a subject of active research (3), and much is known about the encoding of odor identity and concentration (4-6). However, the issue of ranges of favorable odor concentrations has been less studied. A reasonable general hypothesis is that physical sensory limitations set perceptual boundaries, limiting the range of an animal to respond favorably. However, there are instances where differences in odor concentrations can have different meanings: For example, both male and female rodents produce the same pheromone at different concentrations (7), and so males need to be able to distinguish between low and high concentrations. Similarly, a very high concentration might signal an adverse environment with overcrowding, in which case the animal is better off looking elsewhere. In such cases, the concentration preferences of the animals are tuned to some optimal value that has a higher probability of a successful outcome. Here, we show that Caenorhabditis elegans exhibits a striking tuning of pheromone concentration preferences, and that this concentration tuning is actively built and maintained by a single class of male-specific neurons, the cephalic sensory neurons (CEMs).The nervous system of C. elegans is famously compact, with 302 hermaphrodite neurons grouped into 118 classes based on morphology and connectivity (8), and 385 male neurons (9-11). Some classes of neurons are sex-specific (Fig. 1A). Members of a class are typically distinguished from each other by their relative anatomical position, such as left/right and dorsal/ventral. Although initially it was thought that members of a class were functionally similar, ...

mentioning

confidence: 99%

Contrasting responses within a single neuron class enable sex-specific attraction in Caenorhabditis elegans

Narayan

Venkatachalam

Durak

et al. 2016

Self Cite

112

“…Dauers have a thickened cuticle, do not feed, derive energy from fat stores, and up-regulate stress-resistance pathways (6). Certain ascarosides also influence behaviors, including male attraction to hermaphrodites, hermaphrodite attraction to males, avoidance, and aggregation (7)(8)(9)(10)(11)(12). C. elegans senses the ascarosides using several classes of G protein-coupled receptors (GPCRs), which are expressed in specific chemosensory neurons (13,14).…”

mentioning

confidence: 99%

“…Biosynthesis of the side chains of the ascarosides requires peroxisomal β-oxidation cycles that shorten the side chains by two carbons per cycle (11,(17)(18)(19). Four peroxisomal enzymes, an acyl-CoA oxidase (ACOX-1), enoyl-CoA hydratase (MAOC-1), (3R)-hydroxyacyl-CoA dehydrogenase (DHS-28), and 3-ketoacylCoA thiolase (DAF-22), have been implicated in the β-oxidation cycles for ascaroside biosynthesis (Fig.…”

mentioning

confidence: 99%

“…Four peroxisomal enzymes, an acyl-CoA oxidase (ACOX-1), enoyl-CoA hydratase (MAOC-1), (3R)-hydroxyacyl-CoA dehydrogenase (DHS-28), and 3-ketoacylCoA thiolase (DAF-22), have been implicated in the β-oxidation cycles for ascaroside biosynthesis (Fig. 1C) (11,(17)(18)(19). These enzymes are homologous to mammalian peroxisomal enzymes that process very long chain fatty acids, branched-chain fatty acids, and bile acid intermediates (20).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans

Zhang

Feng

Chinta

et al. 2015

158

Caenorhabditis elegans uses ascaroside pheromones to induce development of the stress-resistant dauer larval stage and to coordinate various behaviors. Peroxisomal β-oxidation cycles are required for the biosynthesis of the fatty acid-derived side chains of the ascarosides. Here we show that three acyl-CoA oxidases, which catalyze the first step in these β-oxidation cycles, form different protein homo-and heterodimers with distinct substrate preferences. Mutations in the acyl-CoA oxidase genes acox-1, -2, and -3 led to specific defects in ascaroside production. When the acyl-CoA oxidases were expressed alone or in pairs and purified, the resulting acyl-CoA oxidase homo-and heterodimers displayed different sidechain length preferences in an in vitro activity assay. Specifically, an ACOX-1 homodimer controls the production of ascarosides with side chains with nine or fewer carbons, an ACOX-1/ACOX-3 heterodimer controls the production of those with side chains with seven or fewer carbons, and an ACOX-2 homodimer controls the production of those with ω-side chains with less than five carbons. Our results support a biosynthetic model in which β-oxidation enzymes act directly on the CoA-thioesters of ascaroside biosynthetic precursors. Furthermore, we identify environmental conditions, including high temperature and low food availability, that induce the expression of acox-2 and/or acox-3 and lead to corresponding changes in ascaroside production. Thus, our work uncovers an important mechanism by which C. elegans increases the production of the most potent dauer pheromones, those with the shortest side chains, under specific environmental conditions. dauer | pheromone | ascaroside | beta-oxidation | acyl-CoA oxidase

“…Although HPLC-MS studies have led to the identification of more than 140 pheromones and pheromone-related metabolites in C. elegans (15), little is known about how production of such pheromones is regulated. Life stage and environmental conditions have been shown to affect pheromone output, but the detailed mechanisms remain elusive (16).…”

mentioning

confidence: 99%

Communication between oocytes and somatic cells regulates volatile pheromone production in Caenorhabditis elegans

Leighton

Choe

et al. 2014

Self Cite

Males of the androdioecious species Caenorhabditis elegans are more likely to attempt to mate with and successfully inseminate C. elegans hermaphrodites that do not concurrently harbor sperm. Although a small number of genes have been implicated in this effect, the mechanism by which it arises remains unknown. In the context of the battle of the sexes, it is also unknown whether this effect is to the benefit of the male, the hermaphrodite, or both. We report that successful contact between mature sperm and oocyte in the C. elegans gonad at the start of fertilization causes the oocyte to release a signal that is transmitted to somatic cells in its mother, with the ultimate effect of reducing her attractiveness to males. Changes in hermaphrodite attractiveness are tied to the production of a volatile pheromone, the first such pheromone described in C. elegans.fertilization | sex pheromones | egg-soma communication I ts properties of self-fertilization and rapid generation, along with its extensive library of mutants, make Caenorhabditis elegans an excellent system in which to study reproductive events. The generation time of C. elegans is under 3 d, and a single hermaphroditic worm can use its sperm to fertilize its own eggs, without the need for mating (1). C. elegans and related nematodes have a robust sperm sensation pathway that limits unfruitful oocyte maturation and ovulation (2). Both self-sperm and nonself-sperm secrete protein ligands, known as major sperm proteins (MSPs), that activate signal transduction pathways in both unfertilized oocytes, leading to activation of mitogen-activated protein kinase (MPK-1), and the somatic gonad, involving transcription factor CEH-18. The result of this signaling is the release of oocytes from prophase I arrest and the ovulation of unarrested oocytes into the uterus (3, 4).Several behaviors of female and hermaphroditic nematodes have been demonstrated to correlate with either the presence of sperm or the recentness of mating. C. elegans hermaphrodites that have exhausted their supply of self-sperm are more likely to elicit a mating response from males of their species, and less likely to resist an attempted mating. Mutant C. elegans hermaphrodites that develop without self-sperm also elicit more mating attempts, and this increase in attractiveness vanishes after a successful mating (5, 6). In the gonochoristic species Caenorhabditis brenneri and Caenorhabditis remanei, males are attracted to a volatile pheromone produced only by females that have not recently mated (7). The mechanisms that link these behaviors to sperm status remain unknown.Pheromones have been shown to exist in dozens of nematode species (8-10) and have been positively identified in several, including C. elegans (11-14). Although HPLC-MS studies have led to the identification of more than 140 pheromones and pheromone-related metabolites in C. elegans (15), little is known about how production of such pheromones is regulated. Life stage and environmental conditions have been shown to affect pheromone o...