Complex small-molecule architectures regulate phenotypic plasticity in a nematode

Abstract

Chemistry the worm's way: The nematode Pristionchus pacificus constructs elaborate small molecules from modified building blocks of primary metabolism, including an unusual xylopyranose-based nucleoside (see scheme). These compounds act as signaling molecules to control adult phenotypic plasticity and dauer development and provide examples of modular generation of structural diversity in metazoans.

Figure 1

a) Structures of previously identified small-molecule signals regulating development and behavior in C. elegans. b) P. pacificus exo-metabolome samples induce dauer arrest and affect mouth-form dimorphism, promoting eurystomatous mouth development. We here identify the active components via activity guided fractionation and 2D NMR-spectroscopic profiling.

Figure 2

a) High-resolution HPLC-MS analysis reveals species whose molecular formulae provide additional constraints for structures proposed based on NMR-spectroscopic analysis of the P. pacificus exo-metabolome. b) Major components of the P. pacificus exo-metabolome derived from assembly of building blocks from carbohydrate (black), amino acid (green), and nucleoside (red) metabolism, as well as likely TCA cycle-derived succinate (magenta). Also shown is the related tRNA nucleoside, N⁶-threonylcarbamoyladenosine (t⁶A). c) Abbreviated synthesis scheme for identified P. pacificus metabolites and several non-natural stereoisomers (see Supporting Information for details)

Figure 3

Regulation of mouth dimorphism and dauer induction by synthetic samples of identified P. pacificus metabolites. All experiments were performed in triplicate for each treatment. a, b) Compounds were assayed at 1 µM concentration (*P < 0.01, **P < 0.001). c, d) Compounds with significant activity at 1 µM (P < 0.01) were subsequently tested at a range of concentrations.

Figure 4

Small molecule signaling in nematodes occupies a central position connecting primary metabolism to evolutionarily conserved transcription factors, including DAF-16/FOXO and the nuclear hormone receptor (NHR) DAF-12, a vitamin D and liver X receptor homolog.