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.

Fig. 1.

Chemical structures of components of the dauer pheromone. (A) The chemical structures of ascarosides C6 (1), C9 (2), and C7 (3). (B) Key dqf-COSY and ¹H-¹³C HMBC interactions for ascaroside C3 (4). (C) The chemical structure of ascaroside C3 (4). (D) The synthesis of ascaroside C3 (4) proceeded from dibenzoyl ascarylose (7). An excess of 3-buten-1-ol was first glycosylated with the dibenzoyl ascarylose in the presence of boron trifluoride diethyl etherate to afford the homoallyl ascaroside. The olefin was then cleaved with potassium permanganate to afford the carboxylic acid. Finally, ester hydrolysis with aqueous lithium hydroxide afforded the target compound (4).

Fig. 2.

Biological characterization of synthetic ascaroside C3 (4). (A) Titration of ascaroside C3 (4) in the dauer formation assay at 20°C and 25°C. The data represent the average of two experiments (± 1 SD). (B) Effect of ascarosides C6 (1), C9 (2), C7 (3), and C3 (4) (each at 73 nM), alone or in combination, in the dauer formation assay in wild-type worms at 25°C. The data represent the average of two experiments (± 1 SD). (C) Effect of ascarosides C6 (1), C9 (2), C7 (3), and C3 (4) (each at 220 nM), alone or in combination, in the dauer formation assay in wild-type worms at 20°C. The data represent the average of two experiments (± 1 SD).