Antebi A (2005) Cell Metab "The prepared mind of the worm."

Antebi A

[Cell Metab, 2005]

In C. elegans, dauer pheromone is an indicator of population density and influences pathways that regulate metabolism, development, and aging. In a recent publication in Nature, Paik and coworkers (Jeong et al., 2005) show the purified substance to be a pyran ring conjugated to heptanoic acid, setting the stage for dissecting downstream signaling pathways.

Mari Ohtani et al. (2007) International Worm Meeting "Lifespan extending activity of C. elegans secreta."

Shuji Honda, Mari Ohtani, Yasuo Kimura, Yoko Honda, Tsuyoshi Kawano

[International Worm Meeting, 2007]

In a response to unfavorable growth conditions such as overpopulation and lack of adequate diet, C. elegans ceases development and enters a growth-arrested stage, a kind of larval diapause. The substance that induces the diapause is yielded by the animal and is called dauer-inducing pheromone. The animal uses the pheromone as a chemical mediator to detect overcrowding. In 2005, Jeong and co-workers isolated daumone as a dauer-inducing pheromone and elucidated its structure.1) During our trial of isolating the pheromone, we found lifespan extending activity as well as diapause-inducing activity in a crude extract of C. elegans culture..2) To remove the daumone, the crude extract was subjected to anion-exchange chromatography. The resulting extract also induced an extended lifespan, suggesting that a substance(s) distinct from daumone has lifespan extending activity. The activity disappeared in a daf-16 mutant animal, indicating daf-16 dependency. We are going to check subcellular localization of DAF-16::GFP by the extract. 1) Jeong, P. Y., et al. (2005) Nature 433:541.2) Kawano, T., et al. (2005) Biosci. Biotechnol. Biochem. 69:2479.

Kim HI et al. (2015) Biosci Biotechnol Biochem "In vitro and in vivo antimicrobial efficacy of natural plant-derived compounds against Vibrio cholerae of O1 El Tor Inaba serotype."

Shin OS, Kim HI, Harris JB, Jeong SY, Kim Y, Choi EJ, Son SJ, Kim JA

[Biosci Biotechnol Biochem, 2015]

In this study, we investigated antibacterial activities of 20 plant-derived natural compounds against Gram-negative enteric pathogens. We found that both flavonoids and non-flavonoids, including honokiol and magnolol, possess specific antibacterial activities against V. cholerae, but not against other species of Gram-negative bacterium which we tested. Using various antibacterial assays, we determined that there was a dose-dependent bactericidal and biofilm inhibitory activity of honokiol and magnolol against Vibrio cholerae. In addition to antibacterial activities, these molecules also induced an attenuating effect on reactive oxygen species (ROS) production and pro-inflammatory responses generated by macrophages in response to lipopolysaccharides (LPS). Additionally, Caenorhabditis elegans lethality assay revealed that honokiol and magnolol have an ability to extend a lifespan of V. cholerae-infected worms, contributing to prolonged survival of worms after lethal infection. Altogether, our data show for the first time that honokiol and magnolol may be considered as attractive protective or preventive food adjuncts for cholera.

Lee JI et al. (2003) J Mol Biol "The Caenorhabditis elegans homologue of Down syndrome critical region 1, RCN-1, inhibits multiple functions of the phosphatase calcineurin."

Lee J, Lee JI, Bandyopadhyay J, Ahnn J, Eom SH, Kim DH, Jeong SY, Dhakal BK

[J Mol Biol, 2003]

A conserved family of calcineurin-regulating proteins whose members have been implicated in several disease models such as Down syndrome, Alzheimer's disease, and cardiac hypertrophy has been identified in several organisms including yeast, mice, and humans. We have characterized Caenorhabditis elegans rcn-1, which belongs to this family of calcineurin regulators, and shows approximately 40% identity with the human homologue DSCR-1. rcn-1 is expressed in hypodermal cells, nerve cords and various neurons, vulva epithelial and muscle cells, marginal cells of the pharynx,. and structures of the male tail. rcn-1 expression is upregulated by calcineurin activity. RCN-1 binds to calcineurin A from C. elegans lysate in a calcium-dependent manner, and inhibits bovine calcineurin phosphatase activity dose-dependently. In addition, overexpression of RCN-1 results in calcineurin-deficient phenotypes such as small body size, cuticle defects, fertility defects, slow growth, and serotonin-resistant egg-laying defects. Moreover, phenotypes observed in gain-of-function calcineurin mutant animals were restored to normal by RCN-1 overexpression. These results demostrate an effective and specific inhibition of calcineurin in vitro as well as in vivo by RCN-1.

Rebecca A. Butcher et al. (2007) International Worm Meeting "Small Molecule Signaling of Dauer Formation in C. elegans."

Rebecca A. Butcher, Frank C. Schroeder, Jon Clardy, Masaki Fujita

[International Worm Meeting, 2007]

In response to high population density or low food supply, C. elegans enters an alternative larval stage known as the dauer that can withstand adverse conditions for prolonged periods. C. elegans senses its population density through a small molecule signal, traditionally called the dauer pheromone, that it constitutively secretes into its surroundings. Using activity-guided fractionation and NMR structure elucidation, we determined that the dauer pheromone consists of several structurally related ascarosides, derivatives of the dideoxysugar ascarylose. Two of these ascarosides are roughly two orders of magnitude more potent at inducing dauer formation than a previously reported dauer pheromone component (Jeong et al., Nature, 433: 541, 2005) and constitute a physiologically relevant signal. The ascarosides appear to induce dauer formation in an additive fashion in wild-type worms. The identification of dauer pheromone components that are active at physiologically relevant concentrations will help to identify appropriate receptors and other downstream signaling proteins.

Ludewig A H et al. (2010) Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI "C. elegans Lifespan Extension by Ascarosides Depends on Peroxisomal Beta-oxidation."

Ludewig A H, Malik R U, Schroeder F C

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

Ascarosides are small molecules that constitute major components of the dauer pheromone and act as social signals in C. elegans (Jeong, 2005; Butcher, 2007; Srinivasan, 2008). Chemical analyses have led to the identification of more than ten different ascarosides with dauer-inducing or other signalling activities (Pungaliya, 2009). We recently showed that ascarosides ascr#2 and ascr#3 increase adult lifespan in C. elegans by up to 50%, without reducing fecundity and feeding rate (Ludewig et al, submitted). Biosynthesis of the ascarosides depends on functional peroxisomal beta-oxidation, including daf-22, which encodes a homolog of human sterol carrier protein SCPx and dhs-28, which encodes a homolog of the human D-bifunctional protein.daf-22 and dhs-28 mutant worms do not make dauer-inducing ascarosides and are characterized by a reduced lifespan. These worms accumulate distinct fat granules in the intestine, presumably as a result of defective beta-oxidation of long-chained fatty acids. Here we report that in contrast to wild-type worms, lifespan of daf-22and dhs-28 mutant worms is not increased by ascr#2 and ascr#3. Lifespan of dhs-28(tm2581) mutant worms is largely unaffected by treatment with ascarosides, whereas lifespan of daf-22(ok693) worms decreases in response to exposure to ascarosides.This lifespan decrease is associated by increased accumulation of lipid droplets. Pharyngeal structures are dissolved or greatly enlarged and body length is shortened by up to 30%. Hence, we conclude that peroxisomal beta-oxidation of long-chained fatty acids is required for lifespan extension via ascarosides. 1. P. Jeong et. al., Nature 433, 541-545 (2005). 2. R. Butcher et.al., Nature Chemical Biology 3, 420-422 (2007). 3. J. Srinivasan et.al., Nature 454, 1115-1118 (2008). 4. C. Pungaliya et.al., Proc Natl Acad Sci U S A 106, 7708-7713 (2009).

Park MR et al. (2018) Sci Rep "Probiotic Lactobacillus fermentum strain JDFM216 stimulates the longevity and immune response of Caenorhabditis elegans through a nuclear hormone receptor."

Jeong DY, Kim Y, Kim SH, Maburutse BE, Oh NS, Ryu S, Jeong SY, Park MR, Oh S

[Sci Rep, 2018]

Here, we examined the functionality of Lactobacillus fermentum strain JDFM216, a newly isolated probiotic bacterium, using a Caenorhabditis elegans model. We determined bacterial colonization in the intestinal tract of C. elegans by plate counting and transmission electron microscopy and examined the survival of C. elegans using a solid killing assay. In addition, we employed DNA microarray analysis, quantitative real time-polymerase chain reaction, and immunoblotting assays to explore health-promoting pathways induced by probiotic bacteria in C. elegans. Initially, we found that the probiotic bacterium L. fermentum strain JDFM216 was not harmful to the C. elegans host. Conditioning with JDFM216 led to its colonization in the nematode intestine and enhanced resistance in nematodes exposed to food-borne pathogens, including Staphylococcus aureus and Escherichia coli O157:H7. Interestingly, this probiotic strain significantly prolonged the life span of C. elegans. Whole-transcriptome analysis and transgenic worm assays revealed that the health-promoting effects of JDFM216 were mediated by a nuclear hormone receptor (NHR) family and PMK-1 signaling. Taken together, we described a new C. elegans-based system to screen novel probiotic activity and demonstrated that preconditioning with the probiotic L. fermentum strain JDFM216 may positively stimulate the longevity of the C. elegans host via specific pathway.

Perez-Escudero A et al. (2007) Proc Natl Acad Sci U S A "Optimally wired subnetwork determines neuroanatomy of Caenorhabditis elegans."

de Polavieja GG, Perez-Escudero A

[Proc Natl Acad Sci U S A, 2007]

Wiring cost minimization has successfully explained many structures of nervous systems. However, in the nematode Caenorhabditis elegans, for which anatomical data are most detailed, wiring economy is thought to play only a partial role and alone has failed to account for the grouping of neurons into ganglia [Chen BL, Hall DH, Chklovskii DB (2006) Proc Natl Acad Sci USA 103:4723-4728; Kaiser M, Hilgetag CC (2006) PLoS Comput Biol 2:e95; Ahn Y-Y, Jeong H, Kim BJ (2006) Physica A 367:531-537]. Here, we test the hypothesis that optimally wired subnetworks can exist within nonoptimal networks, thus allowing wiring economy to give an improved prediction of spatial structure. We show in C. elegans that the small subnetwork of wires connecting sensory and motor neurons with sensors and muscles, comprising only 15% of connections, is close to optimal and alone predicts the main features of the spatial segregation of neurons into ganglia and encephalization. Moreover, a method to dissect networks into optimal and nonoptimal components is shown to find a large near-optimal subnetwork of 84% of neurons with a very low position error of 5.4%, and that explains clustering of neurons into ganglia and encephalization to fine detail. In general, we expect realistic networks not to be globally optimal in wire cost. We thus propose the strategy of using near-optimal subnetworks to understand neuroanatomical structure.

Young-Ki Paik et al. (2006) East Asia C. elegans Meeting "A Comprehensive Proteomic Analysis of Dauer and Cholesterol Signaling Pathway in Caenorhabditis elegans"

Mi Jeong Jeong, Young-Ki Paik, Keun Na, Pan-Young Jeong

[East Asia C. elegans Meeting, 2006]

With the availability of its complete genome sequence and unique biological features relevant to human disease, C. elegans has become an invaluable model organism for the studies of proteomics, leading to the elucidation of nematode gene function. We have focused on two key metabolic regulators of C. elegans: dauer-inducing pheromone (daumone; Jeong et al., 2005, Nature, 433, 541-545) and cholesterol (Choi et al, 2003, MCP, 2, 1086-95). First, using various proteomic tools including 2D-LC-MS/MS and DIGE, we analyzed proteomic profiles upon treatment of daumone, which signals C. elegans to enter the dauer stage, an enduring and non-ageing stage of the nematode life cycle. We found that there are multi-level changes in protein expression in the area of energy metabolism (decreased) and oxidative defense system (increased), suggesting that differential changes in various metabolic pathways appear to accommodate this non-aged state. This proteomic data was also paralleled with DNA microarray studies, which provided a window for direct comparison of proteomic and genomic profiles in dauer state. Second, we have launched a global C. elegans proteome project (CEPP) in order to analyze a comprehensive map of proteins involved in cholesterol signaling pathway in embryonic stage of C. elegans. In this talk, we will discuss a few lessons as well as some progress obtained from the pilot phase with respect to data management and functional annotation in C. elegans

Lee JH et al. (1991) International C. elegans Meeting "ROLE OF UNC-101 IN C.ELEGANS VULVAL DEVELOPMENT"

Jongeward GD, Lee JH, Sternberg PW

[International C. elegans Meeting, 1991]

We previously isolated two unc-101 alleles (e.g. syl O8) in a screen for suppressors of vulvaless phenotype of let-23. unc-101 mutations also confer an uncoordinated phenotype as well as subviability, defecation and FITC staining defects. We are interested m the genetics and molecular biology of this locus because of its broad range of phenotypes and lts role in vulval development. We isolated a putative null allele of unc-101. We used trimethyl- psoralen as a mutagen in a screen for mutations that fail to complement unc-l Ol (rh6). One new allele, sy 216, was recovered from 11,000 Fl cross-progeny hermaphrodites. This allele is a homozygous Ll larval lethal. Unlike the visible alleles, the lethality of thls allele cannot be maternally rescued. Animals of the genotype sy2161syl O8 are less viable than animals bearing syl O8 in trans to any visible allele. The sy216 Isyl O8 heterozygote is also a good suppressor of the let-23(syl ) vulval defect. Therefore we consider sy216 a putative null allele of unc-101. We believe that the null phenotype of unc-101 is lethality and suppression of let-23. sy216 does not delete unc-75, ced-l and unc-S9, nor does it overlap eDf3. We are currently trying to clone unc-101 using parallel RFLP mapping with the congenic strain used for cloning ced-l, which was kindly provided by Bob Horvitz's lab. We obtained 37 unc-59 nUnc-75 recombinants from unc-75(e950)ced-1(nlS06) +unc-S9 (e290)1 ++unc-lOl( sylO8) + heterozygotes,and southern hybridization analysis with Tcl as probe is underway. [See Figure]