New York Area C. elegans Discussion Group Meeting (1)

Agenda

*Presentation times are subject to change.

Abstracts

Understanding the C. elegans wiring diagram, after (almost) 25 years: perspectives, results, and unanswered questions

Cori Bargmann, PhD, The Rockefeller University

Abstract not supplied

Complexin has opposite effects on two modes of synaptic vesicle fusion

Jeremy Dittman, MD, PhD, Weill Cornell Medical College

Synaptic transmission can occur in a binary or graded fashion depending on whether transmitter release is triggered by action potentials or by gradual changes in membrane potential. Molecular differences of these two types of fusion events and their differential regulation in a physiological context have yet to be addressed. Complexin is a conserved SNARE-binding protein that has been proposed to regulate both spontaneous and stimulus-evoked synaptic vesicle (SV) fusion. Here, we examine complexin function at a graded synapse in C. elegans. Null complexin (cpx-1) mutants are viable although nervous system function is significantly impaired. Loss of CPX-1 results in a 3-fold increase in the rate of tonic synaptic transmission at the neuromuscular junction while stimulus-evoked SV fusion is decreased 10-fold. A truncated CPX-1 missing its C-terminal domain can rescue stimulus-evoked synaptic vesicle exocytosis but fails to suppress tonic activity, demonstrating that these two modes of exocytosis can be distinguished at the molecular level. A SNARE-binding CPX-1 variant also rescues evoked but not tonic neurotransmitter release. Finally, tonic but not evoked release can be rescued in a syntaxin point mutant by removing CPX-1. Rescue of either form of exocytosis partially restores locomotory behavior indicating that both types of synaptic transmission are relevant. These observations suggest a dual role for CPX-1: suppressing SV exocytosis driven by low levels of endogenous neural activity while promoting synchronous fusion of SVs driven by a depolarizing stimulus. Thus, patterns of synaptic activity regulate complexin’s inhibitory and permissive roles at a graded synapse.

Quantitative genetic dissection of thermal avoidance behavior in C. elegans

Rajarshi Ghosh, PhD, Princeton University

Individuals within and between species often exhibit heritable variation in sub-steps of a behavioral sequence. What genetic changes and architecture allow for such plasticity? Does the genetic change alter the connectivity of neural circuitry or logic of a neural circuit operation or both? To address these questions we transiently raised the local temperature around a worm by an IR laser and recorded several aspects of the resulting escape response. Typically upon sensation of a thermal impulse worms exhibit a behavioral sequence in which they enter a pause state followed by reversals and an omega turn and resumption of forward movement. We quantitatively characterized several aspects of this sensori-motor transformation during escape response for the laboratory strain (N2) and a wild isolate (CB4856) of C. elegans for stimuli resulting in 0.3, 0.8, 3 or 7.5ºC rise in temperature. We found that various aspects of response to 0.3ºC increases in temperature exhibited the greatest difference between these two strains. In order to examine the nature and extent of pleiotropy we measured several traits including but not limited to speeds at every 180 milliseconds during the assay, probability of worms switching between various states, duration and number of reversals, probability of a reversal ending in omega turn in recombinant inbred lines made from N2 and CB4856 parent strains. We identified several quantitative trait loci (QTL) underlying different attributes of escape response. For example, the reversal duration and the number of sinusoidal waves during reversals are modulated by one common locus on Chromosome V as well as distinct QTL on Chromosomes IV and X respectively, and the probability of switching to omega turns is regulated by additive QTL on Chromosomes IV and III. Thus the behavioral states resulting from thermal impulse and switching between them are genetically separable. We will discuss the progress made in mapping genes underlying the QTL.

Endogenous RNAi and Insulin-like signaling work in parallel to control neuronal development in C. elegans

Lisa Kennedy, Columbia University Medical Center

We are investigating the biological roles of endogenous RNA interference in Caenorhabditis elegans. Specifically, we have identified migration and axon guidance defects in the hermaphordite-specific neurons (HSNs) in a subset of RNAi pathway mutants. These mutants include the following: an RNAi-promoting chromatin factor, Zinc Finger Protein 1 (ZFP-1); a dsRNA-binding protein of the Dicer complex, RDE-4; a dicer-related helicase (DRH-3) and a nuclear Argonaute, CSR-1, which is chromosome-segregation and RNAi deficient.

Furthermore, we have observed phenotypic similarities between a conserved FOXO family transcription factor, DAF-16, a major transcriptional output repressed by insulin-like signaling and ZFP-1. Among these shared phenotypes are HSN under-migration and axon guidance defects. A daf-16; zfp-1 double mutant exhibits enhanced defects in both axon guidance and HSN under-migration, suggesting that daf-16 and zfp-1 work in parallel genetic pathways to regulate HSN development. Additionally, we have determined that constitutively expressing DAF-16 in the nucleus by removing age-1 activity leads to overmigration of the HSN in a DAF-16 dependent manner, thereby further implicating insulin-like signaling as an important modulator of cell migration in C. elegans.

We are currently investigating candidate targets of both endogenous RNAi components and DAF-16 that may regulate neuronal genes required for proper migration and axon guidance.

Convergent evolution affecting candidate pheromone receptors in Caenorhabditis

Patrick McGrath, PhD, The Rockefeller University

We are using C. elegans as a model for understanding how genetic variation controls phenotypic variation between individuals of a species. In response to high population density and other cues, C. elegans larvae enter the alternative dauer diapause development pathway. Local population density is assessed by animals releasing and sensing a set of closely related pheromones known as ascarosides. We have found that three Caenorhabiditis strains that were grown in liquid culture for long periods have become resistant to dauer pheromones, suggesting that dauer resistance has been positively selected for in these conditions. We mapped the defect in one of these strain and found that it is affected by multiple loci. Part of the defect maps to a deletion of two ASI-expressed chemosensory receptors. Animals lacking these receptors are specifically defective in forming dauers in response to the ascaroside C3, suggesting that they could be C3 pheromone receptors. Independent deletions in these receptors have been identified in each of the three strains that were grown in liquid (two C. elegans strains and one C. briggsae strain), suggesting that adaptation to liquid growth targets the same genes even in species that have been separated for millions of years.

Epidermal Growth Factor Signaling Activates The Ubiquitin Proteasome System In Response To Aging In C. elegans

Chris Rongo, PhD, Rutgers University

Epidermal growth factor (EGF) signaling regulates cell growth, proliferation, and differentiation, and has recently been implicated in regulating lifespan, although the mechanism remains unclear. Here we examine the function of EGF signaling in lifespan in adult C. elegans. We find that EGF signaling regulates lifespan via the Ras-MAPK pathway and the PLZF transcription factors EOR-1 and EOR-2. Using microarray analysis, we found that EGF signaling regulates the expression in adults of genes involved in lipid metabolism, oxidative stress, heat shock response, and the ubiquitin/proteasome system (UPS). We employed GFP-based reporters of both global UPS activity and oxidative stress to test whether EGF signaling alters protein homeostasis, a critical facet in aging and cellular degeneration. We find that EGF signaling triggers an increase in UPS activity and in the levels of polyubiquitinated proteins in epithelial cells as animals mature into adulthood. Through a forward genetic approach, we identified 41 components of the UPS machinery required for this increase in UPS activity, including CHN-1, HECD-1, and UFD-2 (E3/E4 ligases comprising the UFD complex); CUL-1and SKR-5 (F-box E3 ligases); and several ubiquitin-like molecules. Animals that fail to upregulate UPS activity via EGF signaling and the UFD complex have reduced lifespans and indications of oxidative stress. Taken together, our results suggest that EGF signaling and the UFD complex maintain protein homeostasis by augmenting UPS activity as animals mature into adulthood.

*Additional abstracts coming soon.

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