@article {11371, title = {Temporal processing and context dependency in Caenorhabditis elegans response to mechanosensation.}, journal = {Elife}, volume = {7}, year = {2018}, month = {2018 06 26}, abstract = {

A quantitative understanding of how sensory signals are transformed into motor outputs places useful constraints on brain function and helps to reveal the brain\&$\#$39;s underlying computations. We investigate how the nematode Caenorhabditis elegans responds to time-varying mechanosensory signals using a high-throughput optogenetic assay and automated behavior quantification. We find that the behavioral response is tuned to temporal properties of mechanosensory signals, such as their integral and derivative, that extend over many seconds. Mechanosensory signals, even in the same neurons, can be tailored to elicit different behavioral responses. Moreover, we find that the animal\&$\#$39;s response also depends on its behavioral context. Most dramatically, the animal ignores all tested mechanosensory stimuli during turns. Finally, we present a linear-nonlinear model that predicts the animal\&$\#$39;s behavioral response to stimulus.

}, keywords = {Animals, Behavior, Animal, Biophysics, Brain, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Neurons, Optogenetics}, issn = {2050-084X}, doi = {10.7554/eLife.36419}, author = {Liu, Mochi and Sharma, Anuj K and Shaevitz, Joshua W and Leifer, Andrew M} } @article {7611, title = {Automatically tracking neurons in a moving and deforming brain.}, journal = {PLoS Comput Biol}, volume = {13}, year = {2017}, month = {2017 May}, pages = {e1005517}, abstract = {

Advances in optical neuroimaging techniques now allow neural activity to be recorded with cellular resolution in awake and behaving animals. Brain motion in these recordings pose a unique challenge. The location of individual neurons must be tracked in 3D over time to accurately extract single neuron activity traces. Recordings from small invertebrates like C. elegans are especially challenging because they undergo very large brain motion and deformation during animal movement. Here we present an automated computer vision pipeline to reliably track populations of neurons with single neuron resolution in the brain of a freely moving C. elegans undergoing large motion and deformation. 3D volumetric fluorescent images of the animal\&$\#$39;s brain are straightened, aligned and registered, and the locations of neurons in the images are found via segmentation. Each neuron is then assigned an identity using a new time-independent machine-learning approach we call Neuron Registration Vector Encoding. In this approach, non-rigid point-set registration is used to match each segmented neuron in each volume with a set of reference volumes taken from throughout the recording. The way each neuron matches with the references defines a feature vector which is clustered to assign an identity to each neuron in each volume. Finally, thin-plate spline interpolation is used to correct errors in segmentation and check consistency of assigned identities. The Neuron Registration Vector Encoding approach proposed here is uniquely well suited for tracking neurons in brains undergoing large deformations. When applied to whole-brain calcium imaging recordings in freely moving C. elegans, this analysis pipeline located 156 neurons for the duration of an 8 minute recording and consistently found more neurons more quickly than manual or semi-automated approaches.

}, keywords = {Algorithms, Animals, Brain, Caenorhabditis elegans, Cluster Analysis, Imaging, Three-Dimensional, Microscopy, Fluorescence, Neuroimaging, Neurons}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1005517}, author = {Nguyen, Jeffrey P and Linder, Ashley N and Plummer, George S and Shaevitz, Joshua W and Leifer, Andrew M} } @article {2761, title = {Conserved regulators of cognitive aging: From worms to humans.}, journal = {Behav Brain Res}, volume = {322}, year = {2017}, month = {2017 03 30}, pages = {299-310}, abstract = {

Cognitive decline is a major deficit that arises with age in humans. While some research on the underlying causes of these problems can be done in humans, harnessing the strengths of small model systems, particularly those with well-studied longevity mutants, such as the nematode C. elegans, will accelerate progress. Here we review the approaches being used to study cognitive decline in model organisms and show how simple model systems allow the rapid discovery of conserved molecular mechanisms, which will eventually enable the development of therapeutics to slow cognitive aging.

}, keywords = {Animals, Caenorhabditis elegans, Cognitive Aging, Humans, Models, Animal}, issn = {1872-7549}, doi = {10.1016/j.bbr.2016.06.035}, author = {Arey, Rachel N and Murphy, Coleen T} } @article {3951, title = {The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult phenotype regulators.}, journal = {Nature}, volume = {529}, year = {2016}, month = {2016 Jan 07}, pages = {92-6}, abstract = {

Insulin/insulin-like growth factor signalling (IIS) is a critical regulator of an organism{\textquoteright}s most important biological decisions from growth, development, and metabolism to reproduction and longevity. It primarily does so through the activity of the DAF-16 transcription factor (forkhead box O (FOXO) homologue), whose global targets were identified in Caenorhabditis elegans using whole-worm transcriptional analyses more than a decade ago. IIS and FOXO also regulate important neuronal and adult behavioural phenotypes, such as the maintenance of memory and axon regeneration with age, in both mammals and C. elegans, but the neuron-specific IIS/FOXO targets that regulate these functions are still unknown. By isolating adult C. elegans neurons for transcriptional profiling, we identified both the wild-type and IIS/FOXO mutant adult neuronal transcriptomes for the first time. IIS/FOXO neuron-specific targets are distinct from canonical IIS/FOXO-regulated longevity and metabolism targets, and are required for extended memory in IIS daf-2 mutants. The activity of the forkhead transcription factor FKH-9 in neurons is required for the ability of daf-2 mutants to regenerate axons with age, and its activity in non-neuronal tissues is required for the long lifespan of daf-2 mutants. Together, neuron-specific and canonical IIS/FOXO-regulated targets enable the coordinated extension of neuronal activities, metabolism, and longevity under low-insulin signalling conditions.

}, keywords = {Aging, Animals, Axons, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cell Separation, Forkhead Transcription Factors, Insulin, Longevity, Mechanotransduction, Cellular, Memory, Mutation, Neurons, Phenotype, Regeneration, Signal Transduction, Somatomedins, Transcriptome}, issn = {1476-4687}, doi = {10.1038/nature16483}, author = {Kaletsky, Rachel and Lakhina, Vanisha and Arey, Rachel and Williams, April and Landis, Jessica and Ashraf, Jasmine and Murphy, Coleen T} } @article {3941, title = {Feeding the germline.}, journal = {Genes Dev}, volume = {30}, year = {2016}, month = {2016 Feb 01}, pages = {249-50}, abstract = {

Nucleotides are required in order to replicate DNA in the developing germline. Here, Chi and colleagues (pp. 307-320) have used Caernohabditis elegans to identify a GLP-1-dependent checkpoint that senses food (bacterially)-supplied nucleotide levels, arresting reproductive development in the absence of sufficient nucleotide supplies.

}, keywords = {Animals, Caenorhabditis elegans, Glucagon-Like Peptide 1, Nucleotides, Receptors, Notch, Signal Transduction}, issn = {1549-5477}, doi = {10.1101/gad.276980.115}, author = {Shi, Cheng and Murphy, Coleen T} } @article {8646, title = {Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans.}, journal = {Elife}, volume = {5}, year = {2016}, month = {2016 Jul 06}, abstract = {

Metabolic network rewiring is the rerouting of metabolism through the use of alternate enzymes to adjust pathway flux and accomplish specific anabolic or catabolic objectives. Here, we report the first characterization of two parallel pathways for the breakdown of the short chain fatty acid propionate in Caenorhabditis elegans. Using genetic interaction mapping, gene co-expression analysis, pathway intermediate quantification and carbon tracing, we uncover a vitamin B12-independent propionate breakdown shunt that is transcriptionally activated on vitamin B12 deficient diets, or under genetic conditions mimicking the human diseases propionic- and methylmalonic acidemia, in which the canonical B12-dependent propionate breakdown pathway is blocked. Our study presents the first example of transcriptional vitamin-directed metabolic network rewiring to promote survival under vitamin deficiency. The ability to reroute propionate breakdown according to B12 availability may provide C. elegans with metabolic plasticity and thus a selective advantage on different diets in the wild.

}, keywords = {Animals, Caenorhabditis elegans, Metabolic Engineering, Metabolic Networks and Pathways, Propionates, Vitamin B 12 Deficiency}, issn = {2050-084X}, doi = {10.7554/eLife.17670}, author = {Watson, Emma and Olin-Sandoval, Viridiana and Hoy, Michael J and Li, Chi-Hua and Louisse, Timo and Yao, Victoria and Mori, Akihiro and Holdorf, Amy D and Troyanskaya, Olga G and Ralser, Markus and Walhout, Albertha Jm} } @article {3936, title = {The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory.}, journal = {Curr Biol}, volume = {26}, year = {2016}, month = {2016 Mar 07}, pages = {605-15}, abstract = {

Aging is the greatest risk factor for a number of neurodegenerative diseases, such as Alzheimer{\textquoteright}s and Parkinson{\textquoteright}s disease. Furthermore, normal aging is associated with a decline in sensory, motor, and cognitive functions. Emerging evidence suggests that synapse alterations, rather than neuronal cell death, are the causes of neuronal dysfunctions in normal aging and in early stages of neurodegenerative diseases. However, little is known about the mechanisms underlying age-related synaptic decline. Here, we uncover a surprising role of the anterograde molecular motor UNC-104/KIF1A as a key regulator of neural circuit deterioration in aging C. elegans. Through analyses of synapse protein localization, synaptic transmission, and animal behaviors, we find that reduced function of UNC-104 accelerates motor circuit dysfunction with age, whereas upregulation of UNC-104 significantly improves motor function at advanced ages and also mildly extends lifespan. In addition, UNC-104-overexpressing animals outperform wild-type controls in associative learning and memory tests. Further genetic analyses suggest that UNC-104 functions downstream of the DAF-2-signaling pathway and is regulated by the FOXO transcription factor DAF-16, which contributes to the effects of DAF-2 in neuronal aging. Together, our cellular, electrophysiological, and behavioral analyses highlight the importance of axonal transport in the maintenance of synaptic structural integrity and function during aging and raise the possibility of targeting kinesins to slow age-related neural circuit dysfunction.

}, keywords = {Aging, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Insulin, Memory, Nerve Tissue Proteins, Signal Transduction, Synapses}, issn = {1879-0445}, doi = {10.1016/j.cub.2015.12.068}, author = {Li, Ling-Bo and Lei, Haoyun and Arey, Rachel N and Li, Pengpeng and Liu, Jianfeng and Murphy, Coleen T and Xu, X Z Shawn and Shen, Kang} } @article {4581, title = {Whole-brain calcium imaging with cellular resolution in freely behaving Caenorhabditis elegans.}, journal = {Proc Natl Acad Sci U S A}, volume = {113}, year = {2016}, month = {2016 Feb 23}, pages = {E1074-81}, abstract = {

The ability to acquire large-scale recordings of neuronal activity in awake and unrestrained animals is needed to provide new insights into how populations of neurons generate animal behavior. We present an instrument capable of recording intracellular calcium transients from the majority of neurons in the head of a freely behaving Caenorhabditis elegans with cellular resolution while simultaneously recording the animal{\textquoteright}s position, posture, and locomotion. This instrument provides whole-brain imaging with cellular resolution in an unrestrained and behaving animal. We use spinning-disk confocal microscopy to capture 3D volumetric fluorescent images of neurons expressing the calcium indicator GCaMP6s at 6 head-volumes/s. A suite of three cameras monitor neuronal fluorescence and the animal{\textquoteright}s position and orientation. Custom software tracks the 3D position of the animal{\textquoteright}s head in real time and two feedback loops adjust a motorized stage and objective to keep the animal{\textquoteright}s head within the field of view as the animal roams freely. We observe calcium transients from up to 77 neurons for over 4 min and correlate this activity with the animal{\textquoteright}s behavior. We characterize noise in the system due to animal motion and show that, across worms, multiple neurons show significant correlations with modes of behavior corresponding to forward, backward, and turning locomotion.

}, keywords = {Animals, Behavior, Animal, Caenorhabditis elegans, Calcium, Molecular Imaging, Neurons}, issn = {1091-6490}, doi = {10.1073/pnas.1507110112}, author = {Nguyen, Jeffrey P and Shipley, Frederick B and Linder, Ashley N and Plummer, George S and Liu, Mochi and Setru, Sagar U and Shaevitz, Joshua W and Leifer, Andrew M} } @article {6391, title = {The cell biology of againg}, journal = {Nat Commun}, volume = {6}, year = {2015}, month = {2015 Nov 20}, pages = {8919}, abstract = {

Ageing is marked by physical decline. Caenorhabditis elegans is a valuable model for identifying genetic regulatory mechanisms of ageing and longevity. Here we report a simple method to assess C. elegans\&$\#$39; maximum physical ability based on the worms\&$\#$39; maximum movement velocity. We show maximum velocity declines with age, correlates well with longevity, accurately reports movement ability and, if measured in mid-adulthood, is predictive of maximal lifespan. Contrary to recent findings, we observe that maximum velocity of worm with mutations in daf-2(e1370) insulin/IGF-1 signalling scales with lifespan. Because of increased odorant receptor expression, daf-2(e1370) mutants prefer food over exploration, causing previous on-food motility assays to underestimate movement ability and, thus, worm health. Finally, a disease-burden analysis of published data reveals that the daf-2(e1370) mutation improves quality of life, and therefore combines lifespan extension with various signs of an increased healthspan.

}, keywords = {Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Female, Insulin, Insulin-Like Growth Factor I, Longevity, Male, Mutation, Receptor, Insulin, Signal Transduction}, issn = {2041-1723}, doi = {10.1038/ncomms9919}, author = {Hahm, Jeong-Hoon and Kim, Sunhee and DiLoreto, Race and Shi, Cheng and Lee, Seung-Jae V and Murphy, Coleen T and Nam, Hong Gil} } @article {5511, title = {The cell biology of aging.}, journal = {Mol Biol Cell}, volume = {26}, year = {2015}, month = {2015 12 15}, pages = {4524-31}, abstract = {

One of the original hypotheses of organismal longevity posits that aging is the natural result of entropy on the cells, tissues, and organs of the animal--a slow, inexorable slide into nonfunctionality caused by stochastic degradation of its parts. We now have evidence that aging is instead at least in part genetically regulated. Many mutations have been discovered to extend lifespan in organisms of all complexities, from yeast to mammals. The study of metazoan model organisms, such as Caenorhabditis elegans, has been instrumental in understanding the role of genetics in the cell biology of aging. Longevity mutants across the spectrum of model organisms demonstrate that rates of aging are regulated through genetic control of cellular processes. The regulation and subsequent breakdown of cellular processes represent a programmatic decision by the cell to either continue or abandon maintenance procedures with age. Our understanding of cell biological processes involved in regulating aging have been particularly informed by longevity mutants and treatments, such as reduced insulin/IGF-1 signaling and dietary restriction, which are critical in determining the distinction between causes of and responses to aging and have revealed a set of downstream targets that participate in a range of cell biological activities. Here we briefly review some of these important cellular processes.

}, keywords = {Aging, Animals, Caenorhabditis elegans, Gene Expression Regulation, Humans, Insulin, Insulin-Like Growth Factor I, Longevity, Mutation, Signal Transduction}, issn = {1939-4586}, doi = {10.1091/mbc.E14-06-1084}, author = {DiLoreto, Race and Murphy, Coleen T} } @article {3946, title = {Cell-Specific Transcriptional Profiling of Ciliated Sensory Neurons Reveals Regulators of Behavior and Extracellular Vesicle Biogenesis.}, journal = {Curr Biol}, volume = {25}, year = {2015}, month = {2015 Dec 21}, pages = {3232-8}, abstract = {

Cilia and extracellular vesicles (EVs) are signaling organelles [1]. Cilia act as cellular sensory antennae, with defects resulting in human ciliopathies. Cilia both release and bind to EVs [1]. EVs are sub-micron-sized particles released by cells and function in both short- and long-range intercellular communication. In C. elegans and mammals, the autosomal dominant polycystic kidney disease (ADPKD) gene products polycystin-1 and polycystin-2 localize to both cilia and EVs, act in the same genetic pathway, and function in a sensory capacity, suggesting ancient conservation [2]. A fundamental understanding of EV biology and the relationship between the polycystins, cilia, and EVs is lacking. To define properties of a ciliated EV-releasing cell, we performed RNA-seq on 27 GFP-labeled EV-releasing neurons (EVNs) isolated from adult C. elegans. We identified 335 significantly overrepresented genes, of which 61 were validated by GFP reporters. The EVN transcriptional profile uncovered new pathways controlling EV biogenesis and polycystin signaling and also identified EV cargo, which included an antimicrobial peptide and ASIC channel. Tumor-necrosis-associated factor (TRAF) homologs trf-1 and trf-2 and the p38 mitogen-activated protein kinase (MAPK) pmk-1 acted in polycystin-signaling pathways controlling male mating behaviors. pmk-1 was also required for EV biogenesis, independent of the innate immunity MAPK signaling cascade. This first high-resolution transcriptome profile of a subtype of ciliated sensory neurons isolated from adult animals reveals the functional components of an EVN.

}, keywords = {Animals, Caenorhabditis elegans, Extracellular Vesicles, Female, Gene Expression Profiling, Male, Organelle Biogenesis, Sensory Receptor Cells, Sexual Behavior, Animal}, issn = {1879-0445}, doi = {10.1016/j.cub.2015.10.057}, author = {Wang, Juan and Kaletsky, Rachel and Silva, Malan and Williams, April and Haas, Leonard A and Androwski, Rebecca J and Landis, Jessica N and Patrick, Cory and Rashid, Alina and Santiago-Martinez, Dianaliz and Gravato-Nobre, Maria and Hodgkin, Jonathan and Hall, David H and Murphy, Coleen T and Barr, Maureen M} } @article {5581, title = {Genetics of Intraspecies Variation in Avoidance Behavior Induced by a Thermal Stimulus in Caenorhabditis elegans.}, journal = {Genetics}, volume = {200}, year = {2015}, month = {2015 08 01}, pages = {1327-39}, abstract = {

Individuals within a species vary in their responses to a wide range of stimuli, partly as a result of differences in their genetic makeup. Relatively little is known about the genetic and neuronal mechanisms contributing to diversity of behavior in natural populations. By studying intraspecies variation in innate avoidance behavior to thermal stimuli in the nematode Caenorhabditis elegans, we uncovered genetic principles of how different components of a behavioral response can be altered in nature to generate behavioral diversity. Using a thermal pulse assay, we uncovered heritable variation in responses to a transient temperature increase. Quantitative trait locus mapping revealed that separate components of this response were controlled by distinct genomic loci. The loci we identified contributed to variation in components of thermal pulse avoidance behavior in an additive fashion. Our results show that the escape behavior induced by thermal stimuli is composed of simpler behavioral components that are influenced by at least six distinct genetic loci. The loci that decouple components of the escape behavior reveal a genetic system that allows independent modification of behavioral parameters. Our work sets the foundation for future studies of evolution of innate behaviors at the molecular and neuronal level.

}, keywords = {Animals, Avoidance Learning, Behavior, Animal, Caenorhabditis elegans, Evolution, Molecular, Genetic Variation, Male, Quantitative Trait Loci, Species Specificity, Temperature}, issn = {1943-2631}, doi = {10.1534/genetics.115.178491}, author = {Ghosh, Rajarshi and Bloom, Joshua S and Mohammadi, Aylia and Schumer, Molly E and Andolfatto, Peter and Ryu, William and Kruglyak, Leonid} } @article {4321, title = {RNA transcription modulates phase transition-driven nuclear body assembly.}, journal = {Proc Natl Acad Sci U S A}, volume = {112}, year = {2015}, month = {2015 Sep 22}, pages = {E5237-45}, abstract = {

Nuclear bodies are RNA and protein-rich, membraneless organelles that play important roles in gene regulation. The largest and most well-known nuclear body is the nucleolus, an organelle whose primary function in ribosome biogenesis makes it key for cell growth and size homeostasis. The nucleolus and other nuclear bodies behave like liquid-phase droplets and appear to condense from the nucleoplasm by concentration-dependent phase separation. However, nucleoli actively consume chemical energy, and it is unclear how such nonequilibrium activity might impact classical liquid-liquid phase separation. Here, we combine in vivo and in vitro experiments with theory and simulation to characterize the assembly and disassembly dynamics of nucleoli in early Caenorhabditis elegans embryos. In addition to classical nucleoli that assemble at the transcriptionally active nucleolar organizing regions, we observe dozens of "extranucleolar droplets" (ENDs) that condense in the nucleoplasm in a transcription-independent manner. We show that growth of nucleoli and ENDs is consistent with a first-order phase transition in which late-stage coarsening dynamics are mediated by Brownian coalescence and, to a lesser degree, Ostwald ripening. By manipulating C. elegans cell size, we change nucleolar component concentration and confirm several key model predictions. Our results show that rRNA transcription and other nonequilibrium biological activity can modulate the effective thermodynamic parameters governing nucleolar and END assembly, but do not appear to fundamentally alter the passive phase separation mechanism.

}, keywords = {Animals, Caenorhabditis elegans, Cell Nucleolus, Cell Nucleus, Cytoplasm, Green Fluorescent Proteins, Intranuclear Inclusion Bodies, Microscopy, Fluorescence, RNA, Ribosomal, Thermodynamics, Transcription, Genetic}, issn = {1091-6490}, doi = {10.1073/pnas.1509317112}, author = {Berry, Joel and Weber, Stephanie C and Vaidya, Nilesh and Haataja, Mikko and Brangwynne, Clifford P} } @article {5716, title = {A size threshold governs Caenorhabditis elegans developmental progression.}, journal = {Proc Biol Sci}, volume = {282}, year = {2015}, month = {2015 Aug 22}, pages = {20151283}, abstract = {

The growth of organisms from humans to bacteria is affected by environmental conditions. However, mechanisms governing growth and size control are not well understood, particularly in the context of changes in food availability in developing multicellular organisms. Here, we use a novel microfluidic platform to study the impact of diet on the growth and development of the nematode Caenorhabditis elegans. This device allows us to observe individual worms throughout larval development, quantify their growth as well as pinpoint the moulting transitions marking successive developmental stages. Under conditions of low food availability, worms grow very slowly, but do not moult until they have achieved a threshold size. The time spent in larval stages can be extended by over an order of magnitude, in agreement with a simple threshold size model. Thus, a critical worm size appears to trigger developmental progression, and may contribute to prolonged lifespan under dietary restriction.

}, keywords = {Animals, Body Size, Caenorhabditis elegans, Diet, Lab-On-A-Chip Devices, Metamorphosis, Biological}, issn = {1471-2954}, doi = {10.1098/rspb.2015.1283}, author = {Uppaluri, Sravanti and Brangwynne, Clifford P} } @article {4616, title = {A Transport Model for Estimating the Time Course of ERK Activation in the C.~elegans Germline.}, journal = {Biophys J}, volume = {109}, year = {2015}, month = {2015 Dec 01}, pages = {2436-45}, abstract = {

The Caenorhabditis elegans germline is a well-studied model system for investigating the control of cell fate by signaling pathways. Cell signals at the distal tip of the germline promote cell proliferation; just before the loop, signals couple cell maturation to organism-level nutrient status; at the proximal end of the germline, signals coordinate oocyte maturation and fertilization in the presence of sperm. The latter two events require dual phosphorylation and activation of ERK, the effector molecule of the Ras/MAPK cascade. In C.~elegans, ERK is known as MPK-1. At this point, none of today{\textquoteright}s methods for real-time monitoring of dually phosphorylated MPK-1 are working in the germline. Consequently, quantitative understanding of the MPK-1-dependent processes during germline development is limited. Here, we make a step toward advancing this understanding using a model-based framework that reconstructs the time course of MPK-1 activation from a snapshot of a fixed germline. Our approach builds on a number of recent studies for estimating temporal dynamics from fixed organisms, but takes advantage of the anatomy of the germline to simplify the analysis. Our model predicts that the MPK-1 signal turns on \~{}30~h into germ cell progression and peaks \~{}7~h later.

}, keywords = {Animals, Caenorhabditis elegans, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Germ Cells, Kinetics, MAP Kinase Signaling System, Models, Biological, Protein Transport}, issn = {1542-0086}, doi = {10.1016/j.bpj.2015.10.021}, author = {Mattingly, Henry H and Chen, Jessica J and Arur, Swathi and Shvartsman, Stanislav Y} } @article {2016, title = {Caenorhabditis elegans recognizes a bacterial quorum-sensing signal molecule through the AWCON neuron.}, journal = {J Biol Chem}, volume = {289}, year = {2014}, month = {2014 Sep 19}, pages = {26566-73}, abstract = {

In a process known as quorum sensing, bacteria use chemicals called autoinducers for cell-cell communication. Population-wide detection of autoinducers enables bacteria to orchestrate collective behaviors. In the animal kingdom detection of chemicals is vital for success in locating food, finding hosts, and avoiding predators. This behavior, termed chemotaxis, is especially well studied in the nematode Caenorhabditis elegans. Here we demonstrate that the Vibrio cholerae autoinducer (S)-3-hydroxytridecan-4-one, termed CAI-1, influences chemotaxis in C. elegans. C. elegans prefers V. cholerae that produces CAI-1 over a V. cholerae mutant defective for CAI-1 production. The position of the CAI-1 ketone moiety is the key feature driving CAI-1-directed nematode behavior. CAI-1 is detected by the C. elegans amphid sensory neuron AWC(ON). Laser ablation of the AWC(ON) cell, but not other amphid sensory neurons, abolished chemoattraction to CAI-1. These analyses define the structural features of a bacterial-produced signal and the nematode chemosensory neuron that permit cross-kingdom interaction.

}, keywords = {Animals, Caenorhabditis elegans, Chemoreceptor Cells, Chemotaxis, Ketones, Quorum Sensing, Vibrio cholerae}, issn = {1083-351X}, doi = {10.1074/jbc.M114.573832}, author = {Werner, Kristen M and Perez, Lark J and Ghosh, Rajarshi and Semmelhack, Martin F and Bassler, Bonnie L} } @article {3776, title = {Transcriptionally regulated cell adhesion network dictates distal tip cell directionality.}, journal = {Dev Dyn}, volume = {243}, year = {2014}, month = {2014 Aug}, pages = {999-1010}, abstract = {




}, keywords = {Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cell Adhesion, Cell Movement, Gonads, Integrins}, issn = {1097-0177}, doi = {10.1002/dvdy.24146}, author = {Wong, Ming-Ching and Kennedy, William P and Schwarzbauer, Jean E} } @article {2051, title = {A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation.}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, year = {2013}, month = {2013 Oct 29}, pages = {17981-6}, abstract = {

Quorum sensing is a chemical communication process that bacteria use to regulate collective behaviors. Disabling quorum-sensing circuits with small molecules has been proposed as a potential strategy to prevent bacterial pathogenicity. The human pathogen Pseudomonas aeruginosa uses quorum sensing to control virulence and biofilm formation. Here, we analyze synthetic molecules for inhibition of the two P. aeruginosa quorum-sensing receptors, LasR and RhlR. Our most effective compound, meta-bromo-thiolactone (mBTL), inhibits both the production of the virulence factor pyocyanin and biofilm formation. mBTL also protects Caenorhabditis elegans and human lung epithelial cells from killing by P. aeruginosa. Both LasR and RhlR are partially inhibited by mBTL in vivo and in vitro; however, RhlR, not LasR, is the relevant in vivo target. More potent antagonists do not exhibit superior function in impeding virulence. Because LasR and RhlR reciprocally control crucial virulence factors, appropriately tuning rather than completely inhibiting their activities appears to hold the key to blocking pathogenesis in vivo.

}, keywords = {Animals, Bacterial Proteins, Biofilms, Caenorhabditis elegans, Cell Line, Escherichia coli, Humans, Lactones, Microarray Analysis, Molecular Structure, Pseudomonas aeruginosa, Pyocyanine, Quorum Sensing, Respiratory Mucosa, Sulfur Compounds, Trans-Activators, Virulence}, issn = {1091-6490}, doi = {10.1073/pnas.1316981110}, author = {O{\textquoteright}Loughlin, Colleen T and Miller, Laura C and Siryaporn, Albert and Drescher, Knut and Semmelhack, Martin F and Bassler, Bonnie L} } @article {10101, title = {A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage.}, journal = {Proc Natl Acad Sci U S A}, volume = {107}, year = {2010}, month = {2010 Oct 26}, pages = {18475-80}, abstract = {

Many proteins that respond to DNA damage are recruited to DNA lesions. We used a proteomics approach that coupled isotopic labeling with chromatin fractionation and mass spectrometry to uncover proteins that associate with damaged DNA, many of which are involved in DNA repair or nucleolar function. We show that polycomb group members are recruited by poly(ADP ribose) polymerase (PARP) to DNA lesions following UV laser microirradiation. Loss of polycomb components results in IR sensitivity of mammalian cells and Caenorhabditis elegans. PARP also recruits two components of the repressive nucleosome remodeling and deacetylase (NuRD) complex, chromodomain helicase DNA-binding protein 4 (CHD4) and metastasis associated 1 (MTA1), to DNA lesions. PARP plays a role in removing nascent RNA and elongating RNA polymerase II from sites of DNA damage. We propose that PARP sets up a transient repressive chromatin structure at sites of DNA damage to block transcription and facilitate DNA repair.

}, keywords = {Animals, Caenorhabditis elegans, Chromatin, DNA Damage, DNA Repair, HeLa Cells, Humans, In Vitro Techniques, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Poly Adenosine Diphosphate Ribose, Poly(ADP-ribose) Polymerases, Polycomb-Group Proteins, Proteomics, Repressor Proteins, Ultraviolet Rays}, issn = {1091-6490}, doi = {10.1073/pnas.1012946107}, author = {Chou, Danny M and Adamson, Britt and Dephoure, Noah E and Tan, Xu and Nottke, Amanda C and Hurov, Kristen E and Gygi, Steven P and Colai{\'a}covo, Monica P and Elledge, Stephen J} } @article {8556, title = {Crystal structure of the Caenorhabditis elegans apoptosome reveals an octameric assembly of CED-4.}, journal = {Cell}, volume = {141}, year = {2010}, month = {2010 Apr 30}, pages = {446-57}, abstract = {

The CED-4 homo-oligomer or apoptosome is required for initiation of programmed cell death in Caenorhabditis elegans by facilitating autocatalytic activation of the CED-3 caspase zymogen. How the CED-4 apoptosome assembles and activates CED-3 remains enigmatic. Here we report the crystal structure of the complete CED-4 apoptosome and show that it consists of eight CED-4 molecules, organized as a tetramer of an asymmetric dimer via a previously unreported interface among AAA(+) ATPases. These eight CED-4 molecules form a funnel-shaped structure. The mature CED-3 protease is monomeric in solution and forms an active holoenzyme with the CED-4 apoptosome, within which the protease activity of CED-3 is markedly stimulated. Unexpectedly, the octameric CED-4 apoptosome appears to bind only two, not eight, molecules of mature CED-3. The structure of the CED-4 apoptosome reveals shared principles for the NB-ARC family of AAA(+) ATPases and suggests a mechanism for the activation of CED-3.

}, keywords = {Amino Acid Sequence, Animals, Apoptosomes, Apoptotic Protease-Activating Factor 1, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Calcium-Binding Proteins, Caspases, Crystallography, X-Ray, Models, Molecular, Sequence Alignment, X-Ray Diffraction}, issn = {1097-4172}, doi = {10.1016/j.cell.2010.03.017}, author = {Qi, Shiqian and Pang, Yuxuan and Hu, Qi and Liu, Qun and Li, Hua and Zhou, Yulian and He, Tianxi and Liang, Qionglin and Liu, Yexing and Yuan, Xiaoqiu and Luo, Guoan and Li, Huilin and Wang, Jiawei and Yan, Nieng and Shi, Yigong} } @article {2171, title = {A quorum-sensing antagonist targets both membrane-bound and cytoplasmic receptors and controls bacterial pathogenicity.}, journal = {Mol Cell}, volume = {35}, year = {2009}, month = {2009 Jul 31}, pages = {143-53}, abstract = {

Quorum sensing is a process of bacterial communication involving production and detection of secreted molecules called autoinducers. Gram-negative bacteria use acyl-homoserine lactone (AHL) autoinducers, which are detected by one of two receptor types. First, cytoplasmic LuxR-type receptors bind accumulated intracellular AHLs. AHL-LuxR complexes bind DNA and alter gene expression. Second, membrane-bound LuxN-type receptors bind accumulated extracellular AHLs. AHL-LuxN complexes relay information internally by phosphorylation cascades that direct gene expression changes. Here, we show that a small molecule, previously identified as an antagonist of LuxN-type receptors, is also a potent antagonist of the LuxR family, despite differences in receptor structure, localization, AHL specificity, and signaling mechanism. Derivatives were synthesized and optimized for potency, and in each case, we characterized the mode of action of antagonism. The most potent antagonist protects Caenorhabditis elegans from quorum-sensing-mediated killing by Chromobacterium violaceum, validating the notion that targeting quorum sensing has potential for antimicrobial drug development.

}, keywords = {Animals, Anti-Bacterial Agents, Bacterial Proteins, Caenorhabditis elegans, Chromobacterium, Escherichia coli, Inhibitory Concentration 50, Microbial Sensitivity Tests, Quorum Sensing, Receptors, Cell Surface, Receptors, Cytoplasmic and Nuclear, Repressor Proteins, Trans-Activators}, issn = {1097-4164}, doi = {10.1016/j.molcel.2009.05.029}, author = {Swem, Lee R and Swem, Danielle L and O{\textquoteright}Loughlin, Colleen T and Gatmaitan, Raleene and Zhao, Bixiao and Ulrich, Scott M and Bassler, Bonnie L} }