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Analysis of osm-6, a gene that affects sensory cilium structure and sensory neuron function in Caenorhabditis elegans.

ABSTRACT: Mutation in the Caenorhabditis elegans gene osm-6 was previously shown to result in defects in the ultrastructure of sensory cilia and defects in chemosensory and mechanosensory behaviors. We have cloned osm-6 by transposon tagging and transformation rescue and have identified molecular lesions associated with five osm-6 mutations. The osm-6 gene encodes a protein that is 40% identical in amino acid sequence to a predicted mammalian protein of unknown function. We fused osm-6 with the gene for green fluorescent protein (GFP); the fusion gene rescued the osm-6 mutant phenotype and showed accumulation of GFP in ciliated sensory neurons exclusively. The OSM-6::GFP protein was localized to cytoplasm, including processes and dendritic endings where sensory cilia are situated. Mutations in other genes known to cause ciliary defects led to changes in the appearance of OSM-6::GFP in dendritic endings or, in the case of daf-19, reduced OSM-6::GFP accumulation. We conclude from an analysis of genetic mosaics that osm-6 acts cell autonomously in affecting cilium structure.

SUBMITTER: Collet J

PROVIDER: S-EPMC1459801 | biostudies-other | 1998 Jan

REPOSITORIES: biostudies-other

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Analysis of osm-6, a gene that affects sensory cilium structure and sensory neuron function in Caenorhabditis elegans.

Collet J J Spike C A CA Lundquist E A EA Shaw J E JE Herman R K RK

Genetics 19980101 1

Mutation in the Caenorhabditis elegans gene osm-6 was previously shown to result in defects in the ultrastructure of sensory cilia and defects in chemosensory and mechanosensory behaviors. We have cloned osm-6 by transposon tagging and transformation rescue and have identified molecular lesions associated with five osm-6 mutations. The osm-6 gene encodes a protein that is 40% identical in amino acid sequence to a predicted mammalian protein of unknown function. We fused osm-6 with the gene for g ...[more]

PMID: 9475731

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Project description:Neuromodulators, such as serotonin (5-HT), alter neuronal excitability and synaptic strengths, and define different behavioral states. Neuromodulator-dependent changes in neuronal activity patterns are frequently measured using calcium reporters because calcium imaging can easily be performed on intact functioning nervous systems. With only 302 neurons, the nematode Caenorhabditis elegans provides a relatively simple, yet powerful, system to understand neuromodulation at the level of individual neurons. C. elegans hermaphrodites are repelled by 1-octanol, and the initiation of these aversive responses is potentiated by 5-HT. 5-HT acts on the ASH polymodal nociceptors that sense the 1-octanol stimulus. Surprisingly, 5-HT suppresses ASH Ca2+ transients while simultaneously potentiating 1-octanol-dependent ASH depolarization. Here we further explore this seemingly inverse relationship. Our results show the following (1) 5-HT acts downstream of depolarization, through Gαq-mediated signaling and calcineurin, to inhibit L-type voltage-gated Ca2+ channels; (2) the 1-octanol-evoked Ca2+ transients in ASHs inhibit depolarization; and (3) the Ca2+-activated K+ channel, SLO-1, acts downstream of 5-HT and is a critical regulator of ASH response dynamics. These findings define a Ca2+-dependent inhibitory feedback loop that can be modulated by 5-HT to increase neuronal excitability and regulate behavior, and highlight the possibility that neuromodulator-induced changes in the amplitudes of Ca2+ transients do not necessarily predict corresponding changes in depolarization.SIGNIFICANCE STATEMENT Neuromodulators, such as 5-HT, modify behavior by regulating excitability and synaptic efficiency in neurons. Neuromodulation is often studied using Ca2+ imaging, whereby neuromodulator-dependent changes in neuronal activity levels can be detected in intact, functioning circuits. Here we show that 5-HT reduces the amplitude of depolarization-dependent Ca2+ transients in a C. elegans nociceptive neuron, through Gαq signaling and calcineurin but that Ca2+ itself inhibits depolarization, likely through Ca2+-activated K+ channels. The net effect of 5-HT, therefore, is to increase neuronal excitability through disinhibition. These results establish a novel 5-HT signal transduction pathway, and demonstrate that neuromodulators can change Ca2+ signals and depolarization amplitudes in opposite directions, simultaneously, within a single neuron.

Project description:We propose a mathematical and computational model that captures the stimulus-generated Ca2+ transients in the C. elegans ASH sensory neuron. The rationale is to develop a tool that will enable a cross-talk between modeling and experiments, using modeling results to guide targeted experimental efforts. The model is built based on biophysical events and molecular cascades known to unfold as part of neurons' Ca2+ homeostasis mechanism, as well as on Ca2+ signaling events. The state of ion channels is described by their probability of being activated or inactivated, and the remaining molecular states are based on biochemically defined kinetic equations or known biochemical motifs. We estimate the parameters of the model using experimental data of hyperosmotic stimulus-evoked Ca2+ transients detected with a FRET sensor in young and aged worms, unstressed and exposed to oxidative stress. We use a hybrid optimization method composed of a multi-objective genetic algorithm and nonlinear least-squares to estimate the model parameters. We first obtain the model parameters for young unstressed worms. Next, we use these values of the parameters as a starting point to identify the model parameters for stressed and aged worms. We show that the model, in combination with experimental data, corroborates literature results. In addition, we demonstrate that our model can be used to predict ASH response to complex combinations of stimulation pulses. The proposed model includes for the first time the ASH Ca2+ dynamics observed during both "on" and "off" responses. This mathematical and computational effort is the first to propose a dynamic model of the Ca2+ transients' mechanism in C. elegans neurons, based on biochemical pathways of the cell's Ca2+ homeostasis machinery. We believe that the proposed model can be used to further elucidate the Ca2+ dynamics of a key C. elegans neuron, to guide future experiments on C. elegans neurobiology, and to pave the way for the development of more mathematical models for neuronal Ca2+ dynamics.

Dataset Information

Analysis of osm-6, a gene that affects sensory cilium structure and sensory neuron function in Caenorhabditis elegans.

Publications

Analysis of osm-6, a gene that affects sensory cilium structure and sensory neuron function in Caenorhabditis elegans.

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