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1.  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.
DOI: http://dx.doi.org/10.7554/eLife.01948.001
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.
DOI: http://dx.doi.org/10.7554/eLife.01948.002
doi:10.7554/eLife.01948
PMCID: PMC3965213  PMID: 24668170
cilia; electron microscopy; electron tomography; C. elegans
2.  The belly rules the nose: feeding state-dependent modulation of peripheral chemosensory responses 
Summary
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.
doi:10.1016/j.conb.2012.08.001
PMCID: PMC3524363  PMID: 22939570
3.  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.
doi:10.1007/s10059-013-0246-z
PMCID: PMC3837705  PMID: 24048681
dendritic spines; diffusion barrier; primary cilia; protein trafficking; structural plasticity
4.  In Silico Molecular Comparisons of C. elegans and Mammalian Pharmacology Identify Distinct Targets That Regulate Feeding 
PLoS Biology  2013;11(11):e1001712.
This paper takes advantage of similarities between the C. elegans and human pharmacopeia to identify and validate pharmacological targets that regulate C. elegans feeding rates.
Phenotypic screens can identify molecules that are at once penetrant and active on the integrated circuitry of a whole cell or organism. These advantages are offset by the need to identify the targets underlying the phenotypes. Additionally, logistical considerations limit screening for certain physiological and behavioral phenotypes to organisms such as zebrafish and C. elegans. This further raises the challenge of elucidating whether compound-target relationships found in model organisms are preserved in humans. To address these challenges we searched for compounds that affect feeding behavior in C. elegans and sought to identify their molecular mechanisms of action. Here, we applied predictive chemoinformatics to small molecules previously identified in a C. elegans phenotypic screen likely to be enriched for feeding regulatory compounds. Based on the predictions, 16 of these compounds were tested in vitro against 20 mammalian targets. Of these, nine were active, with affinities ranging from 9 nM to 10 µM. Four of these nine compounds were found to alter feeding. We then verified the in vitro findings in vivo through genetic knockdowns, the use of previously characterized compounds with high affinity for the four targets, and chemical genetic epistasis, which is the effect of combined chemical and genetic perturbations on a phenotype relative to that of each perturbation in isolation. Our findings reveal four previously unrecognized pathways that regulate feeding in C. elegans with strong parallels in mammals. Together, our study addresses three inherent challenges in phenotypic screening: the identification of the molecular targets from a phenotypic screen, the confirmation of the in vivo relevance of these targets, and the evolutionary conservation and relevance of these targets to their human orthologs.
Author Summary
Many beneficial pharmacological interventions were first discovered by observing the effects of perturbation of intact biological systems by small organic molecules without a priori knowledge of their targets. This forward pharmacological approach has the advantage of directly identifying new pharmacological agents that are active on complex biological processes. However, because of experimental feasibility, systematic application of this approach is generally limited to small animals such as the roundworm C. elegans and zebrafish, raising the question of whether use of these animals could identify compounds that act on ortholgous mammalian targets. A significant challenge in addressing this question is the determination of the molecular identities of the compounds' targets responsible for the desired phenotypic outcomes. Here we describe a computational approach for target identification based on structural similarities of newly identified compounds to known ligand interactions with mostly mammalian targets. For several of the compounds emerging from a C. elegans phenotypic screen, we predict and confirm mammalian targets using in vitro binding assays. Using genetic and pharmacological assays, we then demonstrate that a subset of these compounds alter C. elegans feeding rates through the C. elegans counterparts of the predicted mammalian targets.
doi:10.1371/journal.pbio.1001712
PMCID: PMC3833878  PMID: 24260022
5.  ENDOCYTOSIS GENES FACILITATE PROTEIN AND MEMBRANE TRANSPORT IN C. ELEGANS SENSORY CILIA 
Current biology : CB  2012;22(6):451-460.
SUMMARY
Background
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.
Results
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.
Conclusions
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.
doi:10.1016/j.cub.2012.01.060
PMCID: PMC3678972  PMID: 22342749
6.  Neuromodulatory state and sex specify alternative behaviors through antagonistic synaptic pathways in C. elegans 
Neuron  2012;75(4):585-592.
SUMMARY
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.
doi:10.1016/j.neuron.2012.06.034
PMCID: PMC3462069  PMID: 22920251
7.  Regulation of response properties and operating range of the AFD thermosensory neurons by cGMP signaling 
Current biology : CB  2011;21(5):353-362.
SUMMARY
Background
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.
Results
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.
Conclusions
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.
doi:10.1016/j.cub.2011.01.053
PMCID: PMC3057529  PMID: 21315599
8.  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.
doi:10.1523/JNEUROSCI.1098-11.2011
PMCID: PMC3167209  PMID: 21832201
9.  A Modular Library of Small Molecule Signals Regulates Social Behaviors in Caenorhabditis elegans 
PLoS Biology  2012;10(1):e1001237.
Comparative metabolomics reveals a modular library of small molecule signals that function as aggregation pheromones in the nematode C. elegans.
The nematode C. elegans is an important model for the study of social behaviors. Recent investigations have shown that a family of small molecule signals, the ascarosides, controls population density sensing and mating behavior. However, despite extensive studies of C. elegans aggregation behaviors, no intraspecific signals promoting attraction or aggregation of wild-type hermaphrodites have been identified. Using comparative metabolomics, we show that the known ascarosides are accompanied by a series of derivatives featuring a tryptophan-derived indole moiety. Behavioral assays demonstrate that these indole ascarosides serve as potent intraspecific attraction and aggregation signals for hermaphrodites, in contrast to ascarosides lacking the indole group, which are repulsive. Hermaphrodite attraction to indole ascarosides depends on the ASK amphid sensory neurons. Downstream of the ASK sensory neuron, the interneuron AIA is required for mediating attraction to indole ascarosides instead of the RMG interneurons, which previous studies have shown to integrate attraction and aggregation signals from ASK and other sensory neurons. The role of the RMG interneuron in mediating aggregation and attraction is thought to depend on the neuropeptide Y-like receptor NPR-1, because solitary and social C. elegans strains are distinguished by different npr-1 variants. We show that indole ascarosides promote attraction and aggregation in both solitary and social C. elegans strains. The identification of indole ascarosides as aggregation signals reveals unexpected complexity of social signaling in C. elegans, which appears to be based on a modular library of ascarosides integrating building blocks derived from lipid β-oxidation and amino-acid metabolism. Variation of modules results in strongly altered signaling content, as addition of a tryptophan-derived indole unit to repellent ascarosides produces strongly attractive indole ascarosides. Our findings show that the library of ascarosides represents a highly developed chemical language integrating different neurophysiological pathways to mediate social communication in C. elegans.
Author Summary
Chemical signaling is an ancient form of inter-organismal communication. The nematode Caenorhabditis elegans exhibits a wide range of social behaviors, including mutual attraction and aggregation, and has served as a useful model towards investigating the signaling pathways that regulate these behaviors. Recent investigations showed that other C. elegans behaviors, like population density sensing and mating, are regulated by small molecule signals called ascarosides. However, it remained unclear whether C. elegans uses small molecules to promote intraspecific attraction and aggregation, despite the presence of extensive neural circuitry regulating these behaviors. In this study, we show that C. elegans uses a specifically modified variant of the ascarosides including an indole unit as a highly potent aggregation pheromone. These indole ascarosides integrate input from two major metabolic pathways, amino acid catabolism and lipid beta-oxidation, suggesting that C. elegans communicates metabolic status via a modular code of small-molecule signals. Our study thus provides evidence for use of a multilayered chemical language for inter-organismal signaling by a model organism. Understanding of chemical signaling in nematodes may aid the development of new treatment approaches for parasitic nematodes, which remain among the most prevalent human disease agents.
doi:10.1371/journal.pbio.1001237
PMCID: PMC3254649  PMID: 22253572
10.  A cellular memory of developmental history generates phenotypic diversity in C. elegans 
Current biology : CB  2010;20(2):149-155.
SUMMARY
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.
doi:10.1016/j.cub.2009.11.035
PMCID: PMC2990539  PMID: 20079644
11.  A Novel Neural Substrate for the Transformation of Olfactory Inputs into Motor Output 
PLoS Biology  2010;8(12):e1000567.
Anatomical and physiological experiments in the lamprey reveal the neural circuit involved in transforming olfactory inputs into motor outputs, which was previously unknown in a vertebrate.
It is widely recognized that animals respond to odors by generating or modulating specific motor behaviors. These reactions are important for daily activities, reproduction, and survival. In the sea lamprey, mating occurs after ovulated females are attracted to spawning sites by male sex pheromones. The ubiquity and reliability of olfactory-motor behavioral responses in vertebrates suggest tight coupling between the olfactory system and brain areas controlling movements. However, the circuitry and the underlying cellular neural mechanisms remain largely unknown. Using lamprey brain preparations, and electrophysiology, calcium imaging, and tract tracing experiments, we describe the neural substrate responsible for transforming an olfactory input into a locomotor output. We found that olfactory stimulation with naturally occurring odors and pheromones induced large excitatory responses in reticulospinal cells, the command neurons for locomotion. We have also identified the anatomy and physiology of this circuit. The olfactory input was relayed in the medial part of the olfactory bulb, in the posterior tuberculum, in the mesencephalic locomotor region, to finally reach reticulospinal cells in the hindbrain. Activation of this olfactory-motor pathway generated rhythmic ventral root discharges and swimming movements. Our study bridges the gap between behavior and cellular neural mechanisms in vertebrates, identifying a specific subsystem within the CNS, dedicated to producing motor responses to olfactory inputs.
Author Summary
Animal behaviors, including locomotion, can be driven by olfactory cues, such as pheromones or food sources. The neural substrate (neuroanatomical connections and physiological signals) that permits the transformation of olfactory inputs into locomotor responses is still unknown in vertebrates. In the present study, we identify such a neural substrate in the lamprey. Here, olfactory signals from the outside world are transmitted to the reticulospinal neurons in the lower brainstem, which provide the descending locomotor command to the spinal cord. We found that this circuit originates in the medial portion of the olfactory bulb and that connections are made in the posterior tuberculum, a ventral diencephalic structure. These inputs are then conveyed to the mesencephalic locomotor region, known to project extensively to brainstem reticulospinal neurons and thereby activate locomotion. Our results illuminate a specific dedicated neural substrate in the brain of lampreys that underlies olfactory-motor responses, which is activated by both food-related or pheromonal olfactory cues. It will be of interest to determine whether such a pathway is preserved in all vertebrates.
doi:10.1371/journal.pbio.1000567
PMCID: PMC3006349  PMID: 21203583
12.  C. elegans: a model system for systems neuroscience 
Current opinion in neurobiology  2009;19(6):637-643.
Summary
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.
doi:10.1016/j.conb.2009.09.009
PMCID: PMC2904967  PMID: 19896359
13.  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.
doi:10.1371/journal.pbio.1000503
PMCID: PMC2953524  PMID: 20967231
14.  Sensory signaling-dependent remodeling of olfactory cilia architecture in C. elegans 
Developmental cell  2008;14(5):762-774.
Summary
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.
doi:10.1016/j.devcel.2008.03.002
PMCID: PMC2442577  PMID: 18477458
Cilia; C. elegans; sensory signaling; intraflagellar transport; BBS proteins
15.  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.
Background
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.
Results
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.
Conclusion
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.
doi:10.1186/1749-8104-2-24
PMCID: PMC2213652  PMID: 17986337

Results 1-15 (15)