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).

Pribadi, A. et al. (2017) International Worm Meeting "A family of novel sulfolipids drives C. elegans defensive responses to a predator."

Liu, Z., Schroeder, F., Srinivasan, J., Pribadi, A., Chalasani, S., Kariya, M.

[International Worm Meeting, 2017]

Animals discover predators in their environment and execute appropriate behaviors to increase survival. We investigated Caenorhabditis elegans' responses to a nematode predator, Pristionchus pacificus. Upon detecting P. pacificus excretions, C. elegans responded with behaviors on multiple timescales - an instantaneous escape behavior and a prolonged reduction in egg laying. In collaboration with the Schroeder lab (Cornell University), we used an activity guided fractionation approach to identify the relevant signals. We found that P. pacificus specifically produces a family of novel sulfated lipids that drive both C. elegans responses. Using cell ablations and calcium imaging, we found that a third of the C. elegans amphid sense organ (ASI, ASJ, ASH and ADL neurons) is involved in detecting predator excretions. Exploiting genetic mutants, we show that cyclic nucleotide gated and transient receptor potential channels function in distinct subsets of neurons to drive C. elegans responses. Finally, we show that a human anti-anxiety drug, Zoloft attenuates C. elegans responses to the predator. These studies show that signaling pathways for processing external threats are likely conserved from worms to mammals. Animals discover predators in their environment and execute appropriate behaviors to increase survival.

Kipreos ET et al. (2000) Genome Biol "The F-box protein family."

Kipreos ET, Pagano M

[Genome Biol, 2000]

SUMMARY: The F-box is a protein motif of approximately 50 amino acids that functions as a site of protein-protein interaction. F-box proteins were first characterized as components of SCF ubiquitin-ligase complexes (named after their main components, Skp I, Cullin, and an F-box protein), in which they bind substrates for ubiquitin-mediated proteolysis. The F-box motif links the F-box protein to other components of the SCF complex by binding the core SCF component Skp I. F-box proteins have more recently been discovered to function in non-SCF protein complexes in a variety of cellular functions. There are 11 F-box proteins in budding yeast, 326 predicted in Caenorhabditis elegans, 22 in Drosophila, and at least 38 in humans. F-box proteins often include additional carboxy-terminal motifs capable of protein-protein interaction; the most common secondary motifs in yeast and human F-box proteins are WD repeats and leucine-rich repeats, both of which have been found to bind phosphorylated substrates to the SCF complex. The majority of F-box proteins have other associated motifs, and the functions of most of these proteins have not yet been defined.

Chamberlin HM et al. (1995) Worm Breeder's Gazette "lin-49, An Essential Gene Required For Normal F and U Cells."

Chamberlin HM, Sternberg PW, Baillie DL

[Worm Breeder's Gazette, 1995]

lin-49, an essential gene required for normal F and U cells

Ludewig, A. et al. (2019) International Worm Meeting "Molecular mechanisms underlying pheromone-mediated lifespan regulation in C. elegans."

Pulido, C., Schroeder, F., Ludewig, A.

[International Worm Meeting, 2019]

Previous studies demonstrated that both C. elegans sexes excrete pheromones that alter development and lifespan in the worms. Hermaphrodites produce the dauer-inducing pheromones ascr#2 and ascr#3 which have been shown to increase C. elegans lifespan and stress resistance (Ludewig et al., 2013), whereas males produce compounds that shorten lifespan in both sexes (Gems et al., 2000, Maures et al., 2014) including the ascaroside ascr#10 and the recently identified nacq#1, a representative of a new class of pheromones derived from acylated amino acids (Ludewig et al., in revision). Here we aim to unravel the molecular mechanisms underlying lifespan regulation mediated by ascarosides signaling. We provide evidence that changes in lifespan after exposure to asccr#2, #3 and #10 required G-protein coupled receptors srbc-64 and srbc-66 as well as intact ASK and ASI amphid neurons. Downstream of chemosensory perception, we show that several sirtuins are required for ascaroside-mediated changes of lifespan. Sirtuins are a family of NAD+ dependent histone deacetylases that are involved with regulation of stress responses and longevity in many organisms. Sensing of lifespan-increasing ascarosides results in a sirtuin-dependent transient increase of reactive oxygen species (ROS) levels in the mitochondria. Furthermore, we show that ascaroside-mediated lifespan increase requires the transcription factor skn-1/Nrf, a key regulator of responses to oxidative stress, consistent with a model in which sirtuin-dependent increase of mitochondrial ROS triggers skn-1-activated longevity pathways. In addition, we present the effect of tissue-specific expression of sir-2.1 in neuronal and intestinal cells on C. elegans lifespan. As part of a broader screen for targets of ascaroside signaling, we identified 35 genes differentially expressed in worms after treatment with asrc#3 and ascr#10 by RNAseq. References: Ludewig AH et al. PNAS 2013;110(14):5522-5527. doi:10.1073/pnas.1214467110 Gems D, Riddle DL. Genetics. 2000;154(4):1597-1610. Maures TJ et al. Science. 2013;343(6170):541-544. doi:10.1126/science.1244160

Muschiol D et al. (2009) BMC Ecol "Life cycle and population growth rate of Caenorhabditis elegans studied by a new method."

Schroeder F, Traunspurger W, Muschiol D

[BMC Ecol, 2009]

BACKGROUND: The free-living nematode Caenorhabditis elegans is the predominant model organism in biological research, being used by a huge number of laboratories worldwide. Many researchers have evaluated life-history traits of C. elegans in investigations covering quite different aspects such as ecotoxicology, inbreeding depression and heterosis, dietary restriction/supplement, mutations, and ageing. Such traits include juvenile growth rates, age at sexual maturity, adult body size, age-specific fecundity/mortality, total reproduction, mean and maximum lifespan, and intrinsic population growth rates. However, we found that in life-cycle experiments care is needed regarding protocol design. Here, we test a recently developed method that overcomes some problems associated with traditional cultivation techniques. In this fast and yet precise approach, single individuals are maintained within hanging drops of semi-fluid culture medium, allowing the simultaneous investigation of various life-history traits at any desired degree of accuracy. Here, the life cycles of wild-type C. elegans strains N2 (Bristol, UK) and MY6 (Munster, Germany) were compared at 20 degrees C with 5 x 10(9) Escherichia coli ml-1 as food source. RESULTS: High-resolution life tables and fecundity schedules of the two strains are presented. Though isolated 700 km and 60 years apart from each other, the two strains barely differed in life-cycle parameters. For strain N2 (n = 69), the intrinsic rate of natural increase (r m d(-1)), calculated according to the Lotka equation, was 1.375, the net reproductive rate (R 0) 291, the mean generation time (T) 90 h, and the minimum generation time (T min) 73.0 h. The corresponding values for strain MY6 (n = 72) were r m = 1.460, R0 = 289, T = 84 h, and T min = 67.3 h. Peak egg-laying rates in both strains exceeded 140 eggs d(-1). Juvenile and early adulthood mortality was negligible. Strain N2 lived, on average, for 16.7 d, while strain MY6 died 2 days earlier; however, differences in survivorship curves were statistically non-significant. CONCLUSION: We found no evidence that adaptation to the laboratory altered the life history traits of C. elegans strain N2. Our results, discussed in the light of earlier studies on C. elegans, demonstrate certain advantages of the hanging drop method in investigations of nematode life cycles. Assuming that its reproducibility is validated in further studies, the method will reduce the inter-laboratory variability of life-history estimates and may ultimately prove to be more convenient than the current standard methods used by C. elegans researchers.

Bennett JL et al. (1988) Parasitol Today "Pharmacology of ivermectin."

Williams JF, Bennett JL, Dave V

[Parasitol Today, 1988]

Ivermectin is a semi-synthetic macrocyclic lactone (Fig. I) active in single low doses against many parasites - particularly nematodes and arthropods. It has been registered for animal health use since early 1985, and was earlier this year approved for human use by the French Directorate o f Pharmacy and Drugs. Of particular interest is ivermectin's potential as a micro filaricide for treatment o f onchocerciasis. Clinical trials leave little doubt about the potential o f ivermectin as a therapeutic tool for symptomatic relief from the effects o f infection with Onchocerca volvulus, and the drug is also recognized to have potential in reducing transmission o f the parasite. The manufacturers (Merck, Sharp and Dohme) recently arranged to provide the drug free o f charge to the WHO for mass trials against onchocerciasis in 12 African and Central American countries. In this article we focus on the pharmacological properties o f ivermectin, with a brief consideration of its absorption, fate, excretion and side-effects, and a discussion o f its micro filaricidal action.

Chang, C. et al. (2019) International Worm Meeting "Genetics screens identified npa-1 and cwp-5 play a role in inducing trap-morphogenesis in the nematode-trapping fungus Arthrobotrys oligospora."

Schroeder, F, Hsueh, Y, Chang, C.

[International Worm Meeting, 2019]

The nematode-trapping fungus Arthrobotrys oligospora can sense the presence of the nematode prey. When A. oligospora is exposed to C. elegans, trap morphogenesis is induced. Previous studies showed that ascarosides, a group of conserved nematode pheromones, are sufficient to induce trap morphogenesis in A. oligospora. However, the C. elegans daf-22 mutant which is defective in the production of most ascarosides, is still capable of triggering trap morphogenesis, suggesting that additional cues from the nematodes can be recognized. To identify the potential non-ascaroside factors from C. elegans that trigger trap morphogenesis, we used ethyl methanesulfonate mutagenized the daf-22 mutant and screened for mutants that exhibited decreased trap induction ability in A. oligospora. Approximately 27,000 F2 mutagenized nematodes were isolated, and 16,000 of which were screened to test their ability to induce traps. Three mutants that induced fewer traps than daf-22 were isolated. We used genetic mapping and whole-genome sequencing to identify the mutations that caused decreased trap induction phenotype in the mutant that exhibited the strongest phenotype and identified loss-of-function mutations in cwp-5 and npa-1. Clean deletion mutants of cwp-5 and npa-1 were generated via CRISPR-Cas9 and the mutants were found to induce fewer traps in A. oligosporathan the wild-type N2 strain, suggesting that these two genes play a role in the fungal-nematode communication.

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.

Rehain K et al. (2015) Curr Biol "Neuron migration: anillin protects leading edge actin."

Maddox AS, Rehain K

[Curr Biol, 2015]

Establishment of a neuronal system requires proper regulation of the F-actin-rich leading edges of migrating neurons and neurite growth cones. A new study shows that RhoG signals through the multi-domain protein anillin to stabilize F-actin in these structures.