A potent dauer pheromone component in Caenorhabditis elegans that acts synergistically with other components

Abstract

In the model organism Caenorhabditis elegans, the dauer pheromone is the primary cue for entry into the developmentally arrested, dauer larval stage. The dauer is specialized for survival under harsh environmental conditions and is considered ''nonaging'' because larvae that exit dauer have a normal life span. C. elegans constitutively secretes the dauer pheromone into its environment, enabling it to sense its population density. Several components of the dauer pheromone have been identified as derivatives of the dideoxy sugar ascarylose, but additional unidentified components of the dauer pheromone contribute to its activity. Here, we show that an ascaroside with a 3-hydroxypropionate side chain is a highly potent component of the dauer pheromone that acts synergistically with previously identified components. Furthermore, we show that the active dauer pheromone components that are produced by C. elegans vary depending on cultivation conditions. Identifying the active components of the dauer pheromone, the conditions under which they are produced, and their mechanisms of action will greatly extend our understanding of how chemosensory cues from the environment can influence such fundamental processes as development, metabolism, and aging in nematodes and in higher organisms.ascaroside ͉ natural product structure elucidation

A shortcut to identifying small molecule signals that regulate behavior and development in Caenorhabditis elegans

“…The ascarosides were initially discovered as major components of the dauer pheromone, a small molecule signal that induces developmental arrest of C. elegans larvae at the highly persistent, ''non-aging'' dauer stage (5)(6)(7). Dauer larvae can persist for many months under harsh environmental conditions before resuming development into adults with a normal lifespan of Ϸ15-20 days (9).…”

“…Two families of endogenous small molecules have recently been shown to serve crucial functions in C. elegans endocrine and exocrine signaling: the dafachronic acids, bile-acid-like steroids that act as ligands of the nuclear hormone receptor DAF-12 (4), and the ascarosides, glycosides of the dideoxysugar ascarylose that regulate development and behavior in C. elegans ( Fig. 1) (5)(6)(7)(8).…”

DANSing with Caenorhabditis elegans

“…In 1982, Golden and Riddle reported the existence of an activity purified from organic extracts of conditioned C. elegans growth medium that promotes C. elegans dauer arrest, referred to as dauer pheromone (6). The molecular components of dauer pheromone have eluded characterization until recently, when 2 groups used activityguided fractionation to characterize related ascarosides with dauer-inducing or cross-over (purple) biological roles for individual molecules; ascr#2, ascr#3, and ascr#5 synergize to induce dauer arrest (9), and ascr#2, ascr#3, and ascr#8 act synergistically as a male mating attractant (4, 10).…”

“…A detailed analysis of other ascarosides present in crude extract revealed the presence of multiple distinct but related ascarosides with dauer-inducing activity (8). Notably, although individual ascarosides induce dauer arrest, combinations of ascarosides have additive or synergistic effects (8,9). Furthermore, the identity of ascarosides purified from crude extracts varies depending on growth conditions (9), suggesting that ascaroside profiles may reflect specific information about environmental conditions.…”

“…Like many small-molecule natural products involved in signaling and regulation activities, dauer pheromone is a mixture of components that act synergistically (9). In such situations, activitybased purification schemes are biased against molecules that do not have significant biological activity as individual chemical entities, but which may synergize with other molecules in vivo.…”