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1.  Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging 
PLoS Genetics  2016;12(12):e1006325.
The majority of cilia are formed and maintained by the highly conserved process of intraflagellar transport (IFT). Mutations in IFT genes lead to ciliary structural defects and systemic disorders termed ciliopathies. Here we show that the severely truncated sensory cilia of hypomorphic IFT mutants in C. elegans transiently elongate during a discrete period of adult aging leading to markedly improved sensory behaviors. Age-dependent restoration of cilia morphology occurs in structurally diverse cilia types and requires IFT. We demonstrate that while DAF-16/FOXO is dispensable, the age-dependent suppression of cilia phenotypes in IFT mutants requires cell-autonomous functions of the HSF1 heat shock factor and the Hsp90 chaperone. Our results describe an unexpected role of early aging and protein quality control mechanisms in suppressing ciliary phenotypes of IFT mutants, and suggest possible strategies for targeting subsets of ciliopathies.
Author Summary
Cilia are ‘antenna-like’ structures that are present on nearly all cell types in animals. These structures are important for sensing and signaling external cues to the cell. Most cilia are formed by a protein transport process called ‘intraflagellar transport’ or IFT. Mutations in IFT genes result in severe cilia defects, and are causal to a large number of diverse human disorders called ciliopathies. Since the genes and processes by which cilia are formed are similar across species, studies in experimental models such as the nematode C. elegans can greatly inform our overall understanding of cilia formation and function. Here we report the surprising observation that the structures and functions of severely defective cilia in nematodes with disrupted IFT genes markedly improve upon aging. We find that protein quality control mechanisms that normally decline in aging are required for this age-dependent recovery of cilia structure. Our results raise the possibility that the effects of some mutations in IFT genes can be bypassed under specific conditions, thereby restoring cilia functions.
PMCID: PMC5131903  PMID: 27906968
2.  Developmental programming modulates olfactory behavior in C. elegans via endogenous RNAi pathways 
eLife  null;5:e11642.
Environmental stress during early development can impact adult phenotypes via programmed changes in gene expression. C. elegans larvae respond to environmental stress by entering the stress-resistant dauer diapause pathway and resume development once conditions improve (postdauers). Here we show that the osm-9 TRPV channel gene is a target of developmental programming and is down-regulated specifically in the ADL chemosensory neurons of postdauer adults, resulting in a corresponding altered olfactory behavior that is mediated by ADL in an OSM-9-dependent manner. We identify a cis-acting motif bound by the DAF-3 SMAD and ZFP-1 (AF10) proteins that is necessary for the differential regulation of osm-9, and demonstrate that both chromatin remodeling and endo-siRNA pathways are major contributors to the transcriptional silencing of the osm-9 locus. This work describes an elegant mechanism by which developmental experience influences adult phenotypes by establishing and maintaining transcriptional changes via RNAi and chromatin remodeling pathways.
eLife digest
Increasing evidence suggests that experiencing stressful environments early on in life can have profound effects on the health and behavior of adults. For example, stressful conditions in the womb have been linked to adult depression and metabolic disorders. These effects are thought to be the result of changes in the way that genes in specific tissues are regulated in the individuals that have experienced the stress. However, it is not clear how a particular stress can cause long-term changes in gene activity in specific tissues.
A microscopic worm called Caenorhabditis elegans is often used as a simple animal model to study how animals develop and behave. Previous studies have shown that adult worms that experienced stress early in life show differences in behavior and gene activity compared to genetically identical worms that did not experience the stress. Here, Sims, Ow et al. asked what signals are required for these changes to happen.
The experiments show that a gene called osm-9 – which plays a role in the nervous system – is less active in sensory nerve cells in worms that experienced stress early on in life. This loss of activity resulted in the worms being unable to respond to a particular odor. Two proteins called DAF-3 and ZFP-1 are able to bind to a section of DNA in the osm-9 gene to decrease its activity in response to stress. These proteins are similar to human proteins that are important for development and are associated with some types of leukemia. Further experiments show that small molecules of ribonucleic acid in the “RNA interference” pathway also help to decrease the activity of osm-9 after stress.
Together, Sims, Ow et al.’s findings suggest that environmental conditions in early life regulate the osm-9 gene through the coordinated effort of DAF-3, ZFP-1 and the RNA interference pathway. The next steps are to investigate how these molecules are able to target osm-9 and to identify other proteins that regulate gene activity in response to stress in early life.
PMCID: PMC4924998  PMID: 27351255
postdauer; dauer; TGF-beta; RNAi; chromatin; osm-9; C. elegans
3.  A Forward Genetic Screen for Molecules Involved in Pheromone-Induced Dauer Formation in Caenorhabditis elegans 
G3: Genes|Genomes|Genetics  2016;6(5):1475-1487.
Animals must constantly assess their surroundings and integrate sensory cues to make appropriate behavioral and developmental decisions. Pheromones produced by conspecific individuals provide critical information regarding environmental conditions. Ascaroside pheromone concentration and composition are instructive in the decision of Caenorhabditis elegans to either develop into a reproductive adult or enter into the stress-resistant alternate dauer developmental stage. Pheromones are sensed by a small set of sensory neurons, and integrated with additional environmental cues, to regulate neuroendocrine signaling and dauer formation. To identify molecules required for pheromone-induced dauer formation, we performed an unbiased forward genetic screen and identified phd (pheromone response-defective dauer) mutants. Here, we describe new roles in dauer formation for previously identified neuronal molecules such as the WD40 domain protein QUI-1 and MACO-1 Macoilin, report new roles for nociceptive neurons in modulating pheromone-induced dauer formation, and identify tau tubulin kinases as new genes involved in dauer formation. Thus, phd mutants define loci required for the detection, transmission, or integration of pheromone signals in the regulation of dauer formation.
PMCID: PMC4856098  PMID: 26976437
C. elegans; dauer; pheromone; che-12; maco-1; qui-1; ttbk
4.  The balance between cytoplasmic and nuclear CaM Kinase-1 signaling controls the operating range of noxious heat avoidance 
Neuron  2014;84(5):983-996.
Through encounters with predators, competitors, and noxious stimuli, animals have evolved defensive responses that minimize injury and are essential for survival. Physiological adaptation modulates the stimulus intensities that trigger such nocifensive behaviors, but the molecular networks that define their operating range are largely unknown. Here, we identify a novel, gain-of-function allele of the cmk-1 CaMKI gene in C. elegans and show that loss of the regulatory domain of the CaMKI enzyme produces thermal analgesia and shifts the operating range for nocifensive heat avoidance to higher temperatures. Such analgesia depends on nuclear CMK-1 signaling, while cytoplasmic CMK-1 signaling lowers the threshold for thermal avoidance. CMK-1 acts downstream of heat detection in thermal receptor neurons and controls neuropeptide release. Our results establish CaMKI as a key regulator of the operating range for nocifensive behaviors, and suggest strategies for producing thermal analgesia through the regulation of CaMKI-dependent signaling.
PMCID: PMC4318703  PMID: 25467982
5.  CaMKI-dependent regulation of sensory gene expression mediates experience-dependent plasticity in the operating range of a thermosensory neuron 
Neuron  2014;84(5):919-926.
Sensory adaptation represents a form of experience-dependent plasticity that allows neurons to retain high sensitivity over a broad dynamic range. The mechanisms by which sensory neuron responses are altered on different timescales during adaptation are unclear. The threshold for temperature-evoked activity in the AFD thermosensory neurons (T*AFD) in C. elegans is set by the cultivation temperature (Tc), and regulated by intracellular cGMP levels. We find that T*AFD adapts on both short and long timescales upon exposure to temperatures warmer than Tc, and that prolonged exposure to warmer temperatures alters expression of AFD-specific receptor guanylyl cyclase genes. These temperature-regulated changes in gene expression are mediated by the CMK-1 CaMKI enzyme which exhibits Tc-dependent nucleocytoplasmic shuttling in AFD. Our results indicate that CaMKI-mediated changes in sensory gene expression contribute to long-term adaptation of T*AFD, and suggest that similar temporally and mechanistically distinct phases may regulate the operating ranges of other sensory neurons.
PMCID: PMC4258139  PMID: 25467978
6.  Sex, age and hunger regulate behavioral prioritization through dynamic modulation of chemoreceptor expression 
Current biology : CB  2014;24(21):2509-2517.
Adaptive behavioral prioritization requires flexible outputs from fixed neural circuits. In C. elegans, the prioritization of feeding vs. mate-searching depends on biological sex (males will abandon food to search for mates, while hermaphrodites will not) as well as developmental stage and feeding status. Previously, we found that males are less attracted than hermaphrodites to the food-associated odorant diacetyl, suggesting that sensory modulation may contribute to behavioral prioritization.
We find that somatic sex acts cell-autonomously to reconfigure the olfactory circuit by regulating a key chemoreceptor, odr-10, in the AWA neurons. Moreover, we find that odr-10 has a significant role in food detection, the regulation of which contributes to sex differences in behavioral prioritization. Overexpression of odr-10 increases male food attraction and decreases off-food exploration; conversely, odr-10 loss impairs food taxis in both sexes. In larvae, both sexes prioritize feeding over exploration; correspondingly, the sexes have equal odr-10 expression and food attraction. Food deprivation, which transiently favors feeding over exploration in adult males, increases male food attraction by activating odr-10 expression. Furthermore, the weak expression of odr-10 in well-fed adult males has important adaptive value, allowing males to efficiently locate mates in a patchy food environment.
We find that modulated expression of a single chemoreceptor plays a key role in naturally occurring variation in the prioritization of feeding and exploration. The convergence of three independent regulatory inputs—somatic sex, age, and feeding status—on chemoreceptor expression highlights sensory function as a key source of plasticity in neural circuits.
PMCID: PMC4254623  PMID: 25438941
Olfaction; sex differences; feeding; behavioral state; behavior genetics; C. elegans
8.  Feeding state-dependent regulation of developmental plasticity via CaMKI and neuroendocrine signaling 
eLife  null;4:e10110.
Information about nutrient availability is assessed via largely unknown mechanisms to drive developmental decisions, including the choice of Caenorhabditis elegans larvae to enter into the reproductive cycle or the dauer stage. In this study, we show that CMK-1 CaMKI regulates the dauer decision as a function of feeding state. CMK-1 acts cell-autonomously in the ASI, and non cell-autonomously in the AWC, sensory neurons to regulate expression of the growth promoting daf-7 TGF-β and daf-28 insulin-like peptide (ILP) genes, respectively. Feeding state regulates dynamic subcellular localization of CMK-1, and CMK-1-dependent expression of anti-dauer ILP genes, in AWC. A food-regulated balance between anti-dauer ILP signals from AWC and pro-dauer signals regulates neuroendocrine signaling and dauer entry; disruption of this balance in cmk-1 mutants drives inappropriate dauer formation under well-fed conditions. These results identify mechanisms by which nutrient information is integrated in a small neuronal network to modulate neuroendocrine signaling and developmental plasticity.
eLife digest
Living organisms have the remarkable ability to adapt to changes in their external environment. For example, when conditions are favorable, the larvae of the tiny roundworm C. elegans rapidly mature into adults and reproduce. However, when faced with starvation, over-crowding or other adverse conditions, they can stop growing and enter a type of stasis called the dauer stage, which enables them to survive in harsh conditions for extended periods of time. The worms enter the dauer stage if they detect high levels of a pheromone mixture that is produced by other worms—which indicates that the local population is over-crowded. However, temperature, food availability, and other environmental cues also influence this decision.
A protein called TGF-β and other proteins called insulin-like peptides are produced by a group of sensory neurons in the worm's head. These proteins usually promote the growth of the worms by increasing the production of particular steroid hormones. However, high levels of the pheromone mixture, an inadequate supply of food and other adverse conditions decrease the expression of the genes that encode these proteins, which allows the worm to enter the dauer state. It is not clear how the worm senses food, nor how this is integrated with the information provided by the pheromones to influence this decision.
To address these questions, Neal et al. studied a variety of mutant worms that lacked proteins involved in different aspects of food sensing. The experiments show that worms missing a protein called CaMKI enter the dauer state even under conditions in which food is plentiful and normal worms continue to grow. CaMKI inhibits entry into the dauer stage by increasing the expression of the genes that encode TGF-β and the insulin-like peptides in sensory neurons in response to food.
Neal et al.'s findings reveal how CaMKI enables information about food availability to be integrated with other environmental cues to influence whether young worms enter the dauer state. Understanding how food sensing is linked to changes in hormone levels will help us appreciate why and how the availability of food has complex effects on animal biology and behavior.
PMCID: PMC4558564  PMID: 26335407
CaMKI; neuroendocrine; dauer; C. elegans
10.  Two chemoreceptors mediate developmental effects of dauer pheromone in C. elegans 
Science (New York, N.Y.)  2009;326(5955):994-998.
Intraspecific chemical communication is mediated by signals called pheromones. C. elegans secretes a mixture of small molecules (collectively termed dauer pheromone) that regulates entry into the alternate dauer larval stage and also modulates adult behavior via as yet unknown receptors. Here, we identify two G protein-coupled receptors (GPCRs) that mediate dauer formation in response to a subset of dauer pheromone components. The SRBC-64 and SRBC-66 GPCRs are members of the large Caenorhabditis-specific SRBC subfamily, and are expressed in the ASK chemosensory neurons, which are required for pheromone-induced dauer formation. Expression of both, but not each receptor alone, confers pheromone-mediated effects on heterologous cells. Identification of dauer pheromone receptors will allow a better understanding of the signaling cascades that transduce the context-dependent effects of ecologically important chemical signals.
PMCID: PMC4448937  PMID: 19797623
11.  Primary Cilia and Dendritic Spines: Different but Similar Signaling Compartments 
Molecules and Cells  2013;36(4):288-303.
Primary non-motile cilia and dendritic spines are cellular compartments that are specialized to sense and transduce environmental cues and presynaptic signals, respectively. Despite their unique cellular roles, both compartments exhibit remarkable parallels in the general principles, as well as molecular mechanisms, by which their protein composition, membrane domain architecture, cellular interactions, and structural and functional plasticity are regulated. We compare and contrast the pathways required for the generation and function of cilia and dendritic spines, and suggest that insights from the study of one may inform investigations into the other of these critically important signaling structures.
PMCID: PMC3837705  PMID: 24048681
dendritic spines; diffusion barrier; primary cilia; protein trafficking; structural plasticity
12.  Cis-regulatory mechanisms of gene expression in an olfactory neuron type in C. elegans 
The generation of cellular diversity is dependent on the precise spatiotemporal regulation of gene expression by both cis- and trans-acting mechanisms. The developmental principles regulating expression of specific gene subsets in individual cell types are not fully understood. Here we define the cis-regulatory mechanisms driving expression of cell-selective and broadly expressed genes in vivo in the AWB olfactory neuron subtype in C. elegans. We identify an element that is necessary to drive expression of neuron-selective chemoreceptor genes in the AWB neurons, and show that this element functions in a context-dependent manner. We find that the expression of broadly expressed sensory neuronal genes in the AWB neurons is regulated by diverse cis- and trans-regulatory mechanisms that act partly in parallel to the pathways governing expression of AWB-selective genes. We further demonstrate that cis-acting mechanisms driving gene expression in the AWB neurons appear to have diverged in related nematode species. Our results provide insights into the cis-regulatory logic driving cell-specific gene expression, and suggest that variations in this logic contribute to the generation of functional diversity.
PMCID: PMC4078920  PMID: 19924784
cis-regulatory motifs; chemoreceptors; olfactory neuron; C. elegans
13.  Sensing temperature 
Current biology : CB  2013;23(8):R304-R307.
PMCID: PMC3685181  PMID: 23618661
14.  A high-resolution morphological and ultrastructural map of anterior sensory cilia and glia in Caenorhabditis elegans 
eLife  2014;3:e01948.
Many primary sensory cilia exhibit unique architectures that are critical for transduction of specific sensory stimuli. Although basic ciliogenic mechanisms are well described, how complex ciliary structures are generated remains unclear. Seminal work performed several decades ago provided an initial but incomplete description of diverse sensory cilia morphologies in C. elegans. To begin to explore the mechanisms that generate these remarkably complex structures, we have taken advantage of advances in electron microscopy and tomography, and reconstructed three-dimensional structures of fifty of sixty sensory cilia in the C. elegans adult hermaphrodite at high resolution. We characterize novel axonemal microtubule organization patterns, clarify structural features at the ciliary base, describe new aspects of cilia–glia interactions, and identify structures suggesting novel mechanisms of ciliary protein trafficking. This complete ultrastructural description of diverse cilia in C. elegans provides the foundation for investigations into underlying ciliogenic pathways, as well as contributions of defined ciliary structures to specific neuronal functions.
eLife digest
To survive, animals must constantly gather information about their surroundings and then decide how to respond. Animals rely on cells called sensory neurons to help them perceive and process this information, and these neurons in most animals have smaller structures called cilia that help them to gather this information. The structures of these cilia can range from simple hair-like rods to complex branched arbors. Defective cilia can lead to cell degeneration and death.
Scientists have identified and determined the functions of many of the 60 sensory neurons with cilia in C. elegans, a tiny roundworm with a simple nervous system. These experiments have revealed that the shapes of these cilia are quite diverse, and that the shape determines the type of information the neurons process. Learning more about how cilia are shaped, and how these shapes allow them to perform specific sensory functions, would give scientists a better understanding of how the brain processes sensory information.
Doroquez et al. have now taken advantage of advances in imaging technology to generate highly detailed three-dimensional reconstructions of the cilia on 50 neurons in the nose of C. elegans. The experiments involved rapidly freezing the worms, slowly replacing the frozen water molecules with a preservative solution, and then embedding in resin. This allowed Doroquez et al. to slice the samples into very thin sections—some 1400 times thinner than a sheet of paper—and then image them with transmission electron microscopy and electron tomography. Finally, all these images were combined in a computer to produce 3D models of the cilia.
The models reveal a wide range of cilia structures, including some that have never been examined in detail before. Doroquez et al. were also able to see detailed structures within the cilia, including compartments that determine which proteins should enter into, or be excluded from, an individual cilium. The models, along with the results of previous studies, suggest that cilia are shaped by genetic factors and also by interactions with the environment. This detailed description of diverse cilia structures should now allow researchers to identify the genes that determine their unique shapes, and explore how specific shapes contribute to specific sensory functions.
PMCID: PMC3965213  PMID: 24668170
cilia; electron microscopy; electron tomography; C. elegans
15.  The belly rules the nose: feeding state-dependent modulation of peripheral chemosensory responses 
Feeding history and the presence of food dramatically alters chemosensory behaviors. Recent results indicate that internal nutritional state can gate peripheral gustatory and olfactory sensory responses to affect behavior. Focusing primarily on recent work in C. elegans and Drosophila, I describe the neuromodulatory mechanisms that translate feeding state information into changes in chemosensory neuron response properties and behavioral output.
PMCID: PMC3524363  PMID: 22939570
16.  Primary Cilia and Dendritic Spines: Different but Similar Signaling Compartments 
Molecules and cells  2013;36(4):10.1007/s10059-013-0246-z.
Primary non-motile cilia and dendritic spines are cellular compartments that are specialized to sense and transduce environmental cues and presynaptic signals, respectively. Despite their unique cellular roles, both compartments exhibit remarkable parallels in the general principles, as well as molecular mechanisms, by which their protein composition, membrane domain architecture, cellular interactions, and structural and functional plasticity are regulated. We compare and contrast the pathways required for the generation and function of cilia and dendritic spines, and suggest that insights from the study of one may inform investigations into the other of these critically important signaling structures.
PMCID: PMC3837705  PMID: 24048681
dendritic spines; diffusion barrier; primary cilia; protein trafficking; structural plasticity
Current biology : CB  2012;22(6):451-460.
Multiple intracellular transport pathways drive the formation, maintenance and function of cilia, a compartmentalised organelle associated with motility, chemo-/mechano-/photo-sensation, and developmental signaling. These pathways include cilium-based intraflagellar transport (IFT) and poorly understood membrane trafficking events. Defects in ciliary transport contribute to the aetiology of human ciliary disease such as Bardet-Biedl syndrome (BBS). In this study, we employ the genetically tractable nematode Caenorhabditis elegans to investigate if endocytosis genes function in cilium formation and/or the transport of ciliary membrane or ciliary proteins.
Here we show that localisation of the clathrin light chain, AP-2 clathrin adaptor, dynamin and RAB-5 endocytic proteins overlaps with a morphologically discrete periciliary membrane compartment associated with sensory cilia. In addition, ciliary transmembrane proteins such as G protein-coupled receptors concentrate at periciliary membranes. Disruption of endocytic gene function causes expansion of ciliary and/or periciliary membranes as well as defects in the ciliary targeting and/or transport dynamics of ciliary transmembrane and IFT proteins. Finally, genetic analyses reveal that the ciliary membrane expansions in dynamin and AP-2 mutants require bbs-8 and rab-8 function, and that sensory signaling and endocytic genes may function in a common pathway to regulate ciliary membrane volume.
These data implicate C. elegans endocytosis proteins localized at the ciliary base in regulating ciliary and periciliary membrane volume, and suggest that membrane retrieval from these compartments is counter-balanced by BBS-8 and RAB-8-mediated membrane delivery.
PMCID: PMC3678972  PMID: 22342749
18.  Neuromodulatory state and sex specify alternative behaviors through antagonistic synaptic pathways in C. elegans 
Neuron  2012;75(4):585-592.
Pheromone responses are highly context-dependent. For example, the C. elegans pheromone ascaroside C9 (ascr#3) is repulsive to wild-type hermaphrodites, attractive to wild-type males, and usually neutral to “social” hermaphrodites with reduced activity of the npr-1 neuropeptide receptor gene. We show here that these distinct behavioral responses arise from overlapping push-pull circuits driven by two classes of pheromone-sensing neurons. The ADL sensory neurons detect C9, and in wild-type hermaphrodites, drive C9 repulsion through their chemical synapses. In npr-1 mutant hermaphrodites, C9 repulsion is reduced by the recruitment of a gap junction circuit that antagonizes ADL chemical synapses. In males, ADL sensory responses are diminished; in addition, a second pheromone-sensing neuron, ASK, antagonizes C9 repulsion. The additive effects of these antagonistic circuit elements generate attractive, repulsive or neutral pheromone responses. Neuronal modulation by circuit state and sex, and flexibility in synaptic output pathways, may permit small circuits to maximize their adaptive behavioral outputs.
PMCID: PMC3462069  PMID: 22920251
19.  Regulation of response properties and operating range of the AFD thermosensory neurons by cGMP signaling 
Current biology : CB  2011;21(5):353-362.
The neuronal mechanisms that encode specific stimulus features in order to elicit defined behavioral responses are poorly understood. C. elegans forms a memory of its cultivation temperature (Tc) and exhibits distinct behaviors in different temperature ranges relative to Tc. In particular, C. elegans tracks isotherms only in a narrow temperature band near Tc. Tc memory is in part encoded by the threshold of responsiveness (T*AFD) of the AFD thermosensory neuron pair to temperature stimuli. However, since AFD thermosensory responses appear to be similar at all examined temperatures above T*AFD, the mechanisms that generate specific behaviors in defined temperature ranges remain to be determined.
Here, we show that the AFD neurons respond to the sinusoidal variations in thermal stimuli followed by animals during isothermal tracking (IT) behavior only in a narrow temperature range near Tc. We find that mutations in the AFD-expressed gcy-8 receptor guanylyl cyclase (rGC) gene result in defects in the execution of IT behavior, and are associated with defects in the responses of the AFD neurons to oscillating thermal stimuli. In contrast, mutations in the gcy-18 or gcy-23 rGCs alter the temperature range in which IT behavior is exhibited. Alteration of intracellular cGMP levels via rGC mutations or addition of cGMP analogs shift the lower and upper ranges of the temperature range of IT behavior in part via alteration in T*AFD.
Our observations provide insights into the mechanisms by which a single sensory neuron type encodes features of a given stimulus to generate different behaviors in defined zones.
PMCID: PMC3057529  PMID: 21315599
20.  Degeneracy and neuromodulation among thermosensory neurons contribute to robust thermosensory behaviors in C. elegans 
Animals must ensure that they can execute behaviors important for physiological homeostasis under constantly changing environmental conditions. The neural mechanisms that regulate this behavioral robustness are not well understood. The nematode C. elegans thermoregulates primarily via modulation of navigation behavior. Upon encountering temperatures higher than its cultivation temperature (Tc), C. elegans exhibits negative thermotaxis towards colder temperatures using a biased random walk strategy. We find that C. elegans exhibits robust negative thermotaxis bias under conditions of varying Tc and temperature ranges. By cell ablation and cell-specific rescue experiments, we show that the ASI chemosensory neurons are newly identified components of the thermosensory circuit, and that different combinations of ASI and the previously identified AFD and AWC thermosensory neurons are necessary and sufficient under different conditions to execute a negative thermotaxis strategy. ASI responds to temperature stimuli within a defined operating range defined by Tc, and signaling from AFD regulates the bounds of this operating range, suggesting that neuromodulation among thermosensory neurons maintains coherence of behavioral output. Our observations demonstrate that a negative thermotaxis navigational strategy can be generated via different combinations of thermosensory neurons acting degenerately, and emphasize the importance of defining context when analyzing neuronal contributions to a behavior.
PMCID: PMC3167209  PMID: 21832201
21.  A cellular memory of developmental history generates phenotypic diversity in C. elegans 
Current biology : CB  2010;20(2):149-155.
Early life experiences have a major impact on adult phenotypes [1–3]. However, the mechanisms by which animals retain a cellular memory of early experience are not well understood. Here we show that adult wild-type C. elegans that transiently passed through the stress-resistant dauer larval stage exhibit distinct gene expression profiles and life history traits, as compared to adult animals that bypassed this stage. Using chromatin immmunoprecipitation experiments coupled with massively parallel sequencing, we find that genome-wide levels of specific histone tail modifications are markedly altered in post-dauer animals. Mutations in subsets of genes implicated in chromatin remodeling abolish, or alter, the observed changes in gene expression and life history traits in post-dauer animals. Modifications to the epigenome as a consequence of early experience may contribute in part to a memory of early experience, and generate phenotypic variation in an isogenic population.
PMCID: PMC2990539  PMID: 20079644
22.  C. elegans: a model system for systems neuroscience 
Current opinion in neurobiology  2009;19(6):637-643.
The nematode C. elegans is an excellent model organism for a systems-level understanding of neural circuits and behavior. Advances in the quantitative analyses of behavior and neuronal activity, and the development of new technologies to precisely control and monitor the workings of interconnected circuits, now allow investigations into the molecular, cellular and systems-level strategies that transform sensory inputs into precise behavioral outcomes.
PMCID: PMC2904967  PMID: 19896359
23.  Genome-Wide Analysis of Light- and Temperature-Entrained Circadian Transcripts in Caenorhabditis elegans 
PLoS Biology  2010;8(10):e1000503.
Transcriptional profiling experiments identify light- and temperature-entrained circadian transcripts in C. elegans.
Most organisms have an endogenous circadian clock that is synchronized to environmental signals such as light and temperature. Although circadian rhythms have been described in the nematode Caenorhabditis elegans at the behavioral level, these rhythms appear to be relatively non-robust. Moreover, in contrast to other animal models, no circadian transcriptional rhythms have been identified. Thus, whether this organism contains a bona fide circadian clock remains an open question. Here we use genome-wide expression profiling experiments to identify light- and temperature-entrained oscillating transcripts in C. elegans. These transcripts exhibit rhythmic expression with temperature-compensated 24-h periods. In addition, their expression is sustained under constant conditions, suggesting that they are under circadian regulation. Light and temperature cycles strongly drive gene expression and appear to entrain largely nonoverlapping gene sets. We show that mutations in a cyclic nucleotide-gated channel required for sensory transduction abolish both light- and temperature-entrained gene expression, implying that environmental cues act cell nonautonomously to entrain circadian rhythms. Together, these findings demonstrate circadian-regulated transcriptional rhythms in C. elegans and suggest that further analyses in this organism will provide new information about the evolution and function of this biological clock.
Author Summary
Daily (circadian) rhythms in behavior and physiology allow organisms to adapt to periodic cues such as light and temperature associated with the rotation of the earth. Subsets of molecular components of the internal clock that drive these rhythms, as well as effector genes for behavioral outputs, also exhibit rhythmic expression in many organisms. While circadian rhythms in behavior have previously been described in the nematode Caenorhabditis elegans, no transcriptional rhythms or clock genes have been identified, leaving open the question of the nature of the clock in this organism. Here, we identify light- and temperature-entrained cycling genes in C. elegans via genome-wide transcriptional profiling. Transcripts showing circadian regulation (including expression with a 24-h period maintained upon removal of the entraining stimulus) and temperature compensation were identified. Light and temperature appear to entrain independent sets of genes. We also identify large sets of light- or temperature-driven genes. Mutations in a channel gene previously implicated in sensory transduction in a small set of sensory neurons abolish entrainment of gene expression by environmental signals. This work demonstrates the presence of circadian transcriptional rhythms in C. elegans, and provides the foundation for future investigations into the underlying mechanisms.
PMCID: PMC2953524  PMID: 20967231
24.  Sensory signaling-dependent remodeling of olfactory cilia architecture in C. elegans 
Developmental cell  2008;14(5):762-774.
Non-motile primary cilia are sensory organelles comprised of a microtubular axoneme and a surrounding membrane sheath that houses signaling molecules. Optimal cellular function requires the precise regulation of axoneme assembly, membrane biogenesis and signaling protein targeting and localization via as yet poorly understood mechanisms. Here we show that sensory signaling is required to maintain the architecture of the specialized AWB olfactory neuron cilia in C. elegans. Decreased sensory signaling results in alteration of axoneme length and expansion of a membraneous structure thereby altering the topological distribution of a subset of ciliary transmembrane signaling molecules. Signaling-regulated alteration of ciliary structures can be bypassed by modulation of intracellular cGMP or calcium levels and requires Kinesin-II-driven intraflagellar transport (IFT), as well as BBS and RAB8-related proteins. Our results suggest that compensatory mechanisms in response to altered levels of sensory activity modulate AWB cilia architecture, revealing remarkable plasticity in the regulation of cilia structure.
PMCID: PMC2442577  PMID: 18477458
Cilia; C. elegans; sensory signaling; intraflagellar transport; BBS proteins
25.  Left-right olfactory asymmetry results from antagonistic functions of voltage-activated calcium channels and the Raw repeat protein OLRN-1 in C. elegans 
Neural Development  2007;2:24.
The left and right AWC olfactory neurons in Caenorhabditis elegans differ in their functions and in their expression of chemosensory receptor genes; in each animal, one AWC randomly takes on one identity, designated AWCOFF, and the contralateral AWC becomes AWCON. Signaling between AWC neurons induces left-right asymmetry through a gap junction network and a claudin-related protein, which inhibit a calcium-regulated MAP kinase pathway in the neuron that becomes AWCON.
We show here that the asymmetry gene olrn-1 acts downstream of the gap junction and claudin genes to inhibit the calcium-MAP kinase pathway in AWCON. OLRN-1, a protein with potential membrane-association domains, is related to the Drosophila Raw protein, a negative regulator of JNK mitogen-activated protein (MAP) kinase signaling. olrn-1 opposes the action of two voltage-activated calcium channel homologs, unc-2 (CaV2) and egl-19 (CaV1), which act together to stimulate the calcium/calmodulin-dependent kinase CaMKII and the MAP kinase pathway. Calcium channel activity is essential in AWCOFF, and the two AWC neurons coordinate left-right asymmetry using signals from the calcium channels and signals from olrn-1.
olrn-1 and voltage-activated calcium channels are mediators and targets of AWC signaling that act at the transition between a multicellular signaling network and cell-autonomous execution of the decision. We suggest that the asymmetry decision in AWC results from the intercellular coupling of voltage-regulated channels, whose cross-regulation generates distinct calcium signals in the left and right AWC neurons. The interpretation of these signals by the kinase cascade initiates the sustained difference between the two cells.
PMCID: PMC2213652  PMID: 17986337

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