Plants have evolved complex chemical strategies to communicate with neighboring plants, prevent infection, repel herbivores and attract pollinators. Many of these compounds (called specialized metabolites (SMs) have medicinal properties, which humans have exploited before the advent of modern pharmacology. Identifying new drug candidates among the myriad of plant SMs continues to be a strategy in drug development. Identifying bioactive SMs requires efficient screening methods and new target identification strategies. Given their coevolutionary history with plants, we surmise that nematodes have the ability to detect many plant SMs and we hypothesize that laboratory studies of nematode behavior can identify plant SMs with therapeutic potential. With a fast generation time, richly annotated genome and well documented chemosensory behaviors, C. elegans is an ideal model system for achieving this goal. With ~1453 GPCRs encoded in its genome, C. elegans is a rich source that we can explore using high-content experimental methods, complemented with molecular and quantitative genetic methods to identify targets of plant SMs.
The Neuroplant Project developed a chemotaxis screening platform that efficiently screens 100s of plant SMs against multiple C. elegans strains. Using this platform, we identified 19 compounds that induce attraction/repulsion in the animal, two of which are known neuromodulators. To link these compounds to their receptors, we are mapping the chemosensory neurons that are needed for chemical attraction/repulsion in the laboratory strain, N2 (Bristol); null alleles of the candidate receptors expressed in those neurons are then screened for loss of behavioral responses. To complement these approaches we are leveraging the natural diversity of C. elegans and the genomic resources made available by the CeENDr project (Cook et al. 2016). As proof of concept we are using our platform to conduct chemotaxis assays with the CB4856 strain (Hawaii) against a panel of compounds known to elicit attraction or repulsion in the N2 lab strain. We plan to extend this work to include 10 additional divergent strains curated by CeNDR to represent the genomic variation among wild C. elegans strains. We will present results for N2 against a panel of 96 compounds and pilot studies comparing the sensitivity of N2 and CB4856 to a set of established chemosensory attractants or repellants.