# Small-molecule signals controlling nematode development

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $236,564

## Abstract

The proposed research program will develop a comprehensive understanding of the chemical structures,
biosynthesis, and mechanism of the secondary metabolites used by the nematode Caenorhabditis elegans to
control its development and physiology. We will focus on two important types of chemical signals: (1) The
dauer pheromone, which C. elegans uses to induce development of the stress-resistant, dauer larval stage at
high population densities. (2) A complex hybrid polyketide/ nonribosomal peptide (PK/NRP), which we have
recently identified and shown is important for starvation-induced larval arrest. The dauer pheromone consists
of several derivatives of the 3,6-dideoxy-L-sugar ascarylose, with different fatty acid-derived side chains.
These ascarosides target G protein-coupled receptors in chemosensory neurons and downregulate the insulin
and TGF pathways, which regulate dauer formation, metabolism, and lifespan in C. elegans. In Aim 1 of this
proposal, we will use a multi-disciplinary approach, including metabolomics, in vitro enzyme assays, organic
synthesis of biosynthetic intermediates, and RNAi-based screens, to provide a general framework for
ascaroside biosynthesis and its regulation. Our preliminary results, which show that secondary metabolism in
C. elegans is closely tied to primary metabolism, have uncovered new, surprising roles for primary metabolic
enzymes in ascaroside biosynthesis. We will investigate how different environmental conditions alter specific
signaling pathways and downstream ascaroside biosynthetic enzymes, in order to modulate the chemical
message that C. elegans communicates to the population. Thus, our work will establish when and how and
why C. elegans produces different pheromones. At the fundamental level, these results will enable
connections to be made regarding how animals respond to a changing environment and modulate their
development and physiology, accordingly. In Aim 2 of this proposal, we will identify a complex hybrid PK/NRP
produced by C. elegans. Although it has been noted that a few animals, including C. elegans, contain
polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) genes, very little is known about
these genes. Thus, we are breaking new ground in our work to characterize the structure, biosynthesis, and
biological role of the PK/NRP. The domains in the C. elegans PKS/NRPS diverge significantly from those
found in bacteria and fungi, and thus, by characterizing these domains, we will uncover unique enzymes and
biosynthetic strategies. Our data suggest that the hybrid PK/NRP acts upstream of the insulin pathway and
facilitates the metabolic changes that need to occur during starvation-induced larval arrest. The ascarosides
and the PK/NRP are conserved chemical signals that are critical for the development and survival of many
nematode species, including parasitic ones. Thus, our work will enable the development of chemical tools to
interfere with the life cycles of parasitic nem...

## Key facts

- **NIH application ID:** 9896885
- **Project number:** 5R01GM118775-05
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Rebecca A Butcher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $236,564
- **Award type:** 5
- **Project period:** 2016-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896885

## Citation

> US National Institutes of Health, RePORTER application 9896885, Small-molecule signals controlling nematode development (5R01GM118775-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896885. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*