Edison AS et al. (2016) Metabolites "The Time Is Right to Focus on Model Organism Metabolomes."

Salek RM, Hall RD, Saito K, Steinbeck C, Edison AS, Mistrik R, Kurland IJ, Viant MR, Reed LK, Karp PD, Sumner LW, Junot C

[Metabolites, 2016]

Model organisms are an essential component of biological and biomedical research that can be used to study specific biological processes. These organisms are in part selected for facile experimental study. However, just as importantly, intensive study of a small number of model organisms yields important synergies as discoveries in one area of science for a given organism shed light on biological processes in other areas, even for other organisms. Furthermore, the extensive knowledge bases compiled for each model organism enable systems-level understandings of these species, which enhance the overall biological and biomedical knowledge for all organisms, including humans. Building upon extensive genomics research, we argue that the time is now right to focus intensively on model organism metabolomes. We propose a grand challenge for metabolomics studies of model organisms: to identify and map all metabolites onto metabolic pathways, to develop quantitative metabolic models for model organisms, and to relate organism metabolic pathways within the context of evolutionary metabolomics, i.e., phylometabolomics. These efforts should focus on a series of established model organisms in microbial, animal and plant research.

Edison AS (2009) Curr Opin Neurobiol "Caenorhabditis elegans pheromones regulate multiple complex behaviors."

Edison AS

[Curr Opin Neurobiol, 2009]

A family of small molecules called ascarosides act as pheromones to control multiple behaviors in the nematode Caenorhabditis elegans. At picomolar concentrations, a synergistic mixture of at least three ascarosides produced by hermaphrodites causes male-specific attraction. At higher concentrations, the same ascarosides, perhaps in a different mixture, induce the developmentally arrested stage known as dauer. The production of ascarosides is strongly dependent on environmental conditions, although relatively little is known about the major variables and mechanisms of their regulation. Thus, male mating and dauer formation are linked through a common set of small molecules whose expression is sensitive to a given microenvironment, suggesting a model by which ascarosides regulate the overall life cycle of C. elegans.

Edison AS et al. (2015) Integr Comp Biol "Metabolomics and Natural-Products Strategies to Study Chemical Ecology in Nematodes."

Clendinen CS, Stupp GS, Ponce FV, Edison AS, Beecher C, Ajredini R

[Integr Comp Biol, 2015]

This review provides an overview of two complementary approaches to identify biologically active compounds for studies in chemical ecology. The first is activity-guided fractionation and the second is metabolomics, particularly focusing on a new liquid chromatography-mass spectrometry-based method called isotopic ratio outlier analysis. To illustrate examples using these approaches, we review recent experiments using Caenorhabditis elegans and related free-living nematodes.

Edison AS et al. (1995) International C. elegans Meeting "Cloning and Sequencing of Multiple Transcripts of a FMRFamide-like Neuropeptide Gene in the Nematode Ascaris suum"

Messinger LA, Edison AS, Stretton AOW

[International C. elegans Meeting, 1995]

Five transcripts of a gene encoding a novel sub-family of six FMRFamide-like neuropeptides in the nematode Ascaris suum have been cloned and sequenced. The translated product of these transcripts is a precursor protein containing two main halves: a relatively hydrophobic region with no obvious peptides and a series of peptides separated by characteristic processing sites. The mature peptides share the C-terminal sequence PGVLRFamide but have different N-terminal sequences. Three of the peptides were previously isolated by immunocytochemistry [Cowden and Stretton, Peptides, in press] and three others are novel sequences. Of the transcripts, four have identical translated regions but differ in the 5' or 3' untranslated regions. A fifth transcript encodes a precursor protein with only the peptide-containing C-terminal domain.

Schroeder F C et al. (2010) Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI "Endogenous Small Molecules Increase Lifespan of Caenorhabditis elegans via SIR-2.1"

Fox B W, Bethke A, Pungaliya C, Malik R U, Schroeder F C, Ludewig A H

[Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI, 2010]

Lifespan in metazoans is regulated by several conserved signaling pathways, including the insulin/insulin-like growth factor and sirtuin pathways. W e have found that components of the dauer pheromone, the ascarosides (Edison 2009), regulate C. elegans adult lifespan and stress resistance. Ascarosides increased lifespan and thermotolerance of wild-type worms by up to 56% and 25%, respectively, without reducing fecundity or feeding rate. These lifespan increases are completely abolished by loss of the histone deacetylase SIR-2.1 or loss of components of peroxisomal fatty acid beta-oxidation, but do not require insulin signaling via the FOXO-homolog DAF-16 or TGF-beta signaling. Our findings establish endogenous small molecules as modulators of sirtuin-dependent pathways that connect longevity and stress resistance with peroxisomal fat metabolism. A. S. Edison, Curr. Opin. Neurobiol. 19(4), 378 (2009).

Malik R U et al. (2010) Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI "Ascarosides ascr#2 and ascr#3 Increase Thermotolerance of Adult C. elegans"

Fox B W, Malik R U, Pungaliya C, Schroeder F C, Ludewig A H

[Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI, 2010]

We investigated whether the ascarosides, major components of the C. elegans dauer pheromone (Edison, 2009), affect stress resistance of adult worms. We found that ascarosides markedly increased survival under oxidative stress and resistance to heat stress (thermotolerance at 35 degC). We further measured pharyngeal pumping rates under heat stress and found that pumping rates of worms on ascaroside plates were significantly higher than on control plates. Next, we asked whether nutritional conditions influence the observed ascaroside-mediated increases of stress resistance. For thermotolerance assays under caloric restriction (CR) conditions, we transferred worms to plates without bacteria before exposure to heat stress. Mean heat stress survival time under CR conditions was higher than for worms with bacteria, in accordance with previous studies demonstrating increased stress resistance under starvation conditions. Notably, addition of ascarosides did not further increase thermotolerance of CR worms. These results show that the worms' metabolic state influences the efficacy of ascarosides in increasing thermotolerance. A. S. Edison, Curr. Opin. Neurobiol. 19(4), 378 (2009).

Messinger LA et al. (1995) International C. elegans Meeting "Evolutionary Patterns in FMRFamide Genes: Implications for Nematode Neurophysiology."

Edison AS, Nelson DL, Messinger LA, Stretton AOW

[International C. elegans Meeting, 1995]

We have sequenced an Ascaris suum gene encoding six peptides related to molluscan FMRFamide neuropeptides (Edison et al., in preparation). As in other FMRFamide-like genes, the peptides are processed from a precursor protein containing multiple peptides. We compared the A. suum sequence to other available FMRFamide-like sequences. Although the sequences of the A. suum and Caenorhabtidis elegans peptides are similar, a phylogenetic analysis of the genes finds no evidence of homology. These and other FMRFamide-like genes appear to have evolved independently through internal reiterations rather than by gene duplication. This study reveals potential patterns of functional diversification in nematode neuropeptides.

Chuman, Tatsuji et al. (2011) International Worm Meeting "Identification of a New Ascaroside, Female Attracting Pheromone in Panagrellus redivivus."

Edison, Arthur S., Choe, Andrea, von Reuss, Stephan, Schroeder, Frank C., Chuman, Tatsuji, Sternberg, Paul W., Kaplan, Fatma, Ajredini, Ramadan, Alborn, Hans

[International Worm Meeting, 2011]

Panagrellus redivivus, a free-living nematode related to the well-known model organism, Caenorhabiditis elegans, has been studied in the laboratory for decades and is therefore useful for comparative biological studies with C. elegans. P. redivivus can be easily cultured in the laboratory using conditions similar to those used for C. elegans, and the two species share many desirable traits such as short generation time. Whereas C. elegans has self-fertilizing hermaphrodites and males, P. redivivus has females and males and requires mating for reproduction. P. redivivus females can specifically attract males and males can specifically attract females but the chemical nature of this attraction has until now not been known. We used a protocol, previously developed for C. elegans, to collect large volume liquid co-cultures with bacterial food as well as biologically active worm water samples of P. redivivus. In addition we developed a robust bioassay to test for female attraction using the worm water samples. By activity-guided fractionation, in combination with NMR and LC-MS analyses, we found a pheromone component, component-1, as a female attractant from its worm water sample. Component-1 is a new ascaroside compound and its structure is elucidated by MS and NMR analyses after purification. The synthesis of component-1 for confirmation of the proposed structure is now undergoing. These results suggest a highly conserved and complex system of nematode pheromones and may one day lead to new approaches to the control of parasitic species1,2). References 1.Srinivasan, J., Kaplan, F., Ajredini, R., Zachariah, C., Alborn, H. T., Teal, P. E., Malik, R. U., Edison, A. S., Sternberg, P. W., and Schroeder, F. C. 2008. A blend of small molecules regulates both mating and development in Caenorhabditits elegans. Nature. 454:1115-1118. 2.Edison, A. S. 2009. Caenorhabditis elegans pheromones regulate multiple complex behaviors, Curr Opin Neurobiol 19, 378-388.

Bifarin, O. et al. (2019) International Worm Meeting "UDP-Glycosyltransferases in Caenorhabditis elegans: Insights into Roles in Xenobiotics Detoxification."

Shaver, A., Edison, A., Bifarin, O.

[International Worm Meeting, 2019]

Uridine 5'-diphospho glucuronosyl or glycosyl transferases (UGTs) are involved in phase II xenobiotics metabolism, where they aid the detoxification of xenobiotics via glycosylation of small molecules. While some UGTs have been implicated in several transcriptomics studies when Caenorhabditis elegans are challenged with xenobiotics, there is very little knowledge of the modifications carried out by specific UGTs. In an effort to improve our knowledge of the roles of UGTs in C. elegans, we sort to identify glycosylation (UGT) genes involved in the detoxification of selected xenobiotics and their respective modifications. In this light, we have developed a high-throughput toxicity and defective glycosylation assay (H-TDGA). H-TDGA incorporates a dead/alive toxicity assay using SYTOX green nucleic acid stain; and assays for defective glycosylation using High Performance Liquid Chromatography-Ultra Violet detector (HPLC-UV), High-Resolution Mass Spectrometry (HRMS), and Nuclear Magnetic Resonance (NMR) experiments, all for the detection of potentially glycosylated metabolites and structural elucidation. Using H-TDGA, we have exposed candidate UGT mutant lines to indole, a metabolite produced by Escherichia coli. Indole is toxic to C. elegans at high concentrations, and wild type animals are able to detoxify the xenobiotic via an N-linked glycosylation. Results of assays with UGT mutant lines will be presented.

Lassegue, Circe et al. (2011) International Worm Meeting "Do ascarosides affect egg-laying behavior in Caenorhabditis elegans?"

Lassegue, Circe, Edison, Arthur, Nimalendran, Rathika, Ajredini, Ramadan

[International Worm Meeting, 2011]

Caenorhabditis elegans, a small transparent nematode that lives in temperate soil environments, is one of the simplest eukaryotic organisms with a nervous system to be studied in great detail. Over recent years, a large number of ascarosides have been identified as signaling molecules in C. elegans (Edison, 2009). Ascaroside levels are affected by worm concentration and available food when developed in "worm water". Ascarosides have been shown to regulate a large number of behaviors in C. elegans including dauer formation (Butcher, et al., 2007), mating behavior ((Srinivasan, et al., 2008), aggregation (Macosko, et al., 2009), and olfaction (Yamada, et al., 2010). Additionally, environmental and homeostatic cues are now being explored to see how these affect nematode egg-laying habits (Schafer et al., 2001). We studied the modulatory effect of several ascarosides on egg-laying behavior and brood size in adult female C. elegans. This study aims to determine the effect of ascarosides on egg-laying behavior in adult C. elegans. A range of concentrations of several synthetic ascarosides as well as natural worm water produced by C. elegans were studied. Standard egg-laying assays and known positive and negative controls were utilized (Koelle, 2004).