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Lee I et al. (2012) PLoS One "Metabolic rate regulates L1 longevity in C. elegans."

You YJ, Hendrix A, Kim J, Lee I, Yoshimoto J

[

PLoS One,

2012]

Animals have to cope with starvation. The molecular mechanisms by which animals survive long-term starvation, however, are not clearly understood. When they hatch without food, C. elegans arrests development at the first larval stage (L1) and survives more than two weeks. Here we show that the survival span of arrested L1s, which we call L1 longevity, is a starvation response regulated by metabolic rate during starvation. A high rate of metabolism shortens the L1 survival span, whereas a low rate of metabolism lengthens it. The longer worms are starved, the slower they grow once they are fed, suggesting that L1 arrest has metabolic costs. Furthermore, mutants of genes that regulate metabolism show altered L1 longevity. Among them, we found that AMP-dependent protein kinase (AMPK), as a key energy sensor, regulates L1 longevity by regulating this metabolic arrest. Our results suggest that L1 longevity is determined by metabolic rate and that AMPK as a master regulator of metabolism controls this arrest so that the animals survive long-term starvation.

Lee I et al. (2010) Genome Res "Predicting genetic modifier loci using functional gene networks."

Marcotte EM, Vavouri T, Shin J, Lee I, Fraser AG, Lehner B

[

Genome Res,

2010]

Most phenotypes are genetically complex, with contributions from mutations in many different genes. Mutations in more than one gene can combine synergistically to cause phenotypic change, and systematic studies in model organisms show that these genetic interactions are pervasive. However, in human association studies such nonadditive genetic interactions are very difficult to identify because of a lack of statistical power--simply put, the number of potential interactions is too vast. One approach to resolve this is to predict candidate modifier interactions between loci, and then to specifically test these for associations with the phenotype. Here, we describe a general method for predicting genetic interactions based on the use of integrated functional gene networks. We show that in both Saccharomyces cerevisiae and Caenorhabditis elegans a single high-coverage, high-quality functional network can successfully predict genetic modifiers for the majority of genes. For C. elegans we also describe the construction of a new, improved, and expanded functional network, WormNet 2. Using this network we demonstrate how it is possible to rapidly expand the number of modifier loci known for a gene, predicting and validating new genetic interactions for each of three signal transduction genes. We propose that this approach, termed network-guided modifier screening, provides a general strategy for predicting genetic interactions. This work thus suggests that a high-quality integrated human gene network will provide a powerful resource for modifier locus discovery in many different diseases.

Lee I et al. (2008) Nat Genet "A single gene network accurately predicts phenotypic effects of gene perturbation in Caenorhabditis elegans."

Lee I, Fraser AG, Crombie C, Marcotte EM, Wong W, Lehner B

[

Nat Genet,

2008]

The fundamental aim of genetics is to understand how an organism''s phenotype is determined by its genotype, and implicit in this is predicting how changes in DNA sequence alter phenotypes. A single network covering all the genes of an organism might guide such predictions down to the level of individual cells and tissues. To validate this approach, we computationally generated a network covering most C. elegans genes and tested its predictive capacity. Connectivity within this network predicts essentiality, identifying this relationship as an evolutionarily conserved biological principle. Critically, the network makes tissue-specific predictions-we accurately identify genes for most systematically assayed loss-of-function phenotypes, which span diverse cellular and developmental processes. Using the network, we identify 16 genes whose inactivation suppresses defects in the retinoblastoma tumor suppressor pathway, and we successfully predict that the dystrophin complex modulates EGF signaling. We conclude that an analogous network for human genes might be similarly predictive and thus facilitate identification of disease genes and rational therapeutic targets.

Lee I et al. (2024) Front Toxicol "Effect of altered production and storage of dopamine on development and behavior in C. elegans."

Martin EL, Dicent J, Depew CR, Bucher ML, Knickerbocker AC, Lee I, Miller GW

[

Front Toxicol,

2024]

INTRODUCTION: The nematode, Caenorhabditis elegans (C. elegans), is an advantageous model for studying developmental toxicology due to its well-defined developmental stages and homology to humans. It has been established that across species, dopaminergic neurons are highly vulnerable to neurotoxicant exposure, resulting in developmental neuronal dysfunction and age-induced degeneration. C. elegans, with genetic perturbations in dopamine system proteins, can provide insight into the mechanisms of dopaminergic neurotoxicants. In this study, we present a comprehensive analysis on the effect of gene mutations in dopamine-related proteins on body size, development, and behavior in C. elegans. METHODS: We studied C. elegans that lack the ability to sequester dopamine (OK411) and that overproduce dopamine (UA57) and a novel strain (MBIA) generated by the genetic crossing of OK411 and UA57, which both lack the ability to sequester dopamine into vesicles and, additionally, endogenously overproduce dopamine. The MBIA strain was generated to address the hypothesis that an endogenous increase in the production of dopamine can rescue deficits caused by a lack of vesicular dopamine sequestration. These strains were analyzed for body size, developmental stage, reproduction, egg laying, motor behaviors, and neuronal health utilizing multiple methods. RESULTS: Our results further implicate proper dopamine synthesis and sequestration in the regulation of C. elegans body size, development through larval stages into gravid adulthood, and motor functioning. Furthermore, our analyses demonstrate that body size in terms of length is distinct from the developmental stage as fully developed gravid adult C. elegans with disruptions in the dopamine system have decreased body lengths. Thus, body size should not be used as a proxy for the developmental stage when designing experiments. DISCUSSION: Our results provide additional evidence that the dopamine system impacts the development, growth, and reproduction in C. elegans. Furthermore, our data suggest that endogenously increasing the production of dopamine mitigates deficits in C. elegans lacking the ability to package dopamine into synaptic vesicles. The novel strain, MBIA, and novel analyses of development and reproduction presented here can be utilized in developmental neurotoxicity experiments.

Lee C et al. (2017) Bio Protoc "Single-molecule RNA Fluorescence in situ Hybridization (smFISH) in Caenorhabditis elegans."

Sorensen EB, Lee C, Seidel HS, Lynch TR, Crittenden SL, Kimble J

[

Bio Protoc,

2017]

Single-molecule RNA fluorescence in situ hybridization (smFISH) is a technique to visualize individual RNA molecules using multiple fluorescently-labeled oligonucleotide probes specific to the target RNA ( Raj et al., 2008 ; Lee et al., 2016a ). We adapted this technique to visualize RNAs in the C. elegans whole adult worm or its germline, which enabled simultaneous recording of nascent transcripts at active transcription sites and mature mRNAs in the cytoplasm ( Lee et al., 2013 and 2016b). Here we describe each step of the smFISH procedure, reagents, and microscope settings optimized for C. elegans extruded gonads.

Yang NC et al. (2019) Int J Mol Sci "The Lifespan Extension Ability of Nicotinic Acid Depends on Whether the Intracellular NAD⁺ Level Is Lower than the Sirtuin-Saturating Concentrations."

Yang NC, Lee I, Cho YH

[

Int J Mol Sci,

2019]

Calorie restriction can extend lifespan by increasing intracellular nicotinamide adenine dinucleotide (NAD+), thereby upregulating the activity of sirtuins (Caenorhabditis elegans Sir-2.1; human SIRT1). Nicotinic acid (NA) can be metabolized to NAD+; however, the calorie restriction mimetic (CRM) potential of NA is unclear. This study explored the ability and mechanism of NA to extend the lifespan of human Hs68 cells and C. elegans. We found that NA can efficiently increase the intracellular NAD+ levels in Hs68 cells and C. elegans; however, NA was only able to extend the lifespan of C. elegans. The steady-state NAD+ level in C. elegans was approximately 55 M. When intracellular NAD+ was increased by a mutation of pme-1 (poly (ADP-ribose) metabolism enzyme 1) or by pretreatment with NAD+ in the medium, the lifespan extension ability of NA disappeared. Additionally, the saturating concentration of NAD+ required by SIRT1 was approximately 200 M; however, the steady-state concentration of NAD+ in Hs68 cells reached up to 460 M. These results demonstrate that the lifespan extension ability of NA depends on whether the intracellular level of NAD+ is lower than the sirtuin-saturating concentration in Hs68 cells and in C. elegans. Thus, the CRM potential of NA should be limited to individuals with lower intracellular NAD+.

Miranda MC et al. (2024) MicroPubl Biol "Investigating the effects of antipsychotic drugs as a treatment for improving the activity of the unc-33 /Dpysl2 gene in C. elegans."

Miranda MC, Hyde J, Holgado A, Salazar K, Bell B

[

MicroPubl Biol,

2024]

Prenatal stress is hypothesized to contribute to the development of schizophrenia. Lee and colleagues determined that prenatal stress in rats decreases levels of Dpysl2, which is found to be inactivated in schizophrenic patients. UNC-33 , the homolog to Dpysl2 in C. elegans , is important for axonal outgrowth and synapse formation. Herein, we study the effects of antipsychotic drugs on developing C.elegans exposed to stress through high temperatures. Results indicate that the unc-33 promoter was not impacted by antipsychotic drug treatment, but the lifespan was decreased.

Yang NC et al. (2023) Int J Mol Sci "The Attenuation of Insulin/IGF-1 Signaling Pathway Plays a Crucial Role in the Myo-Inositol-Alleviated Aging in Caenorhabditis elegans."

Chin CY, Zheng YX, Lee I, Yang NC

[

Int J Mol Sci,

2023]

Myo-Inositol (MI) has been shown to alleviate aging in Caenorhabditis (C). elegans. However, the mechanism by which MI alleviates aging remains unclear. In this study, we investigate whether MI can modulate the PI3K so as to attenuate the insulin/IGF-1 signaling (IIS) pathway and exert the longevity effect. The wild-type C. elegans and two mutants of AKT-1 and DAF-16 were used to explore the mechanism of MI so as to extend the lifespan, as well as to improve the health indexes of pharyngeal pumping and body bend, and an aging marker of autofluorescence in the C. elegans. We confirmed that MI could significantly extend the lifespan of C. elegans. MI also ameliorated the pharyngeal pumping and body bend and decreased autofluorescence. We further adopted the approach to reveal the loss-of-function mutants to find the signaling mechanism of MI. The functions of the lifespan-extending, health-improving, and autofluorescence-decreasing effects of MI disappeared in the AKT-1 and DAF-16 mutants. MI could also induce the nuclear localization of the DAF-16. Importantly, we found that MI could dramatically inhibit the phosphoinositide 3-kinase (PI3K) activity in a dose-dependent manner with an IC50 of 90.2 μM for the p110α isoform of the PI3K and 21.7 μM for the p110β. In addition, the downregulation of the PI3K expression and the inhibition of the AKT phosphorylation by MI was also obtained. All these results demonstrate that MI can inhibit the PI3K activity and downregulate the PI3K expression, and the attenuation of the IIS pathway plays a crucial role for MI in alleviating aging in C. elegans.

Souza ACR et al. (2018) Genes (Basel) "Pathogenesis of the Candida parapsilosis Complex in the Model Host Caenorhabditis elegans."

Colombo AL, Fuchs BB, Jayamani E, Mylonakis E, Souza ACR, Alves VS

[

Genes (Basel),

2018]

Caenorhabditiselegans is a valuable tool as an infection model toward the study of Candida species. In this work, we endeavored to develop a C. elegans-Candidaparapsilosis infection model by using the fungi as a food source. Three species of the C. parapsilosis complex (C.parapsilosis (sensustricto), Candidaorthopsilosis and Candidametapsilosis) caused infection resulting in C. elegans killing. All three strains that comprised the complex significantly diminished the nematode lifespan, indicating the virulence of the pathogens against the host. The infection process included invasion of the intestine and vulva which resulted in organ protrusion and hyphae formation. Importantly, hyphae formation at the vulva opening was not previously reported in C. elegans-Candida infections. Fungal infected worms in the liquid assay were susceptible to fluconazole and caspofungin and could be found to mount an immune response mediated through increased expression of cnc-4, cnc-7, and fipr-22/23. Overall, the C. elegans-C. parapsilosis infection model can be used to model C. parapsilosis host-pathogen interactions.

Fourie R et al. (2021) Front Cell Infect Microbiol "Candida albicans SET3 Plays a Role in Early Biofilm Formation, Interaction With Pseudomonas aeruginosa and Virulence in Caenorhabditis elegans."

Sebolai O, Fourie R, Albertyn J, Pohl CH, Gcilitshana O

[

Front Cell Infect Microbiol,

2021]

The yeast Candida albicans exhibits multiple morphologies dependent on environmental cues. Candida albicans biofilms are frequently polymicrobial, enabling interspecies interaction through proximity and contact. The interaction between C. albicans and the bacterium, Pseudomonas aeruginosa, is antagonistic in vitro, with P. aeruginosa repressing the yeast-to-hyphal switch in C. albicans. Previous transcriptional analysis of C. albicans in polymicrobial biofilms with P. aeruginosa revealed upregulation of genes involved in regulation of morphology and biofilm formation, including SET3, a component of the Set3/Hos2 histone deacetylase complex (Set3C). This prompted the question regarding the involvement of SET3 in the interaction between C. albicans and P. aeruginosa, both in vitro and in vivo. We found that SET3 may influence early biofilm formation by C. albicans and the interaction between C. albicans and P. aeruginosa. In addition, although deletion of SET3 did not alter the morphology of C. albicans in the presence of P. aeruginosa, it did cause a reduction in virulence in a Caenorhabditis elegans infection model, even in the presence of P. aeruginosa.

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