New York Area C. elegans Discussion Group Meeting

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New York Area C. elegans Discussion Group Meeting

Tuesday, February 3, 2009

The New York Academy of Sciences

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The New York Area C. elegans Discussion Group meetings will be held in the evenings from 6:30-8:30 PM and will be followed by a reception to which all participants are welcome. Each meeting will include four presentations by graduate students, post-docs, or by laboratory heads. Talks are selected from area laboratories by the program committee with an emphasis on new and emerging data.

Organizers: Jane Hubbard, Skirball Institute of Biomolecular Medicine; Shai Shaham, The Rockefeller University; Cathy Savage-Dunn Queens College, CUNY

Speakers: Daniel A. Colon-Ramos, Yale University; Ya Fu, Albert Einstein College of Medicine; Carolina Ibanez-Ventoso, Rutgers University; Maria-Halima Laaberki, Columbia University

Abstracts

Building a behavioral circuit: Molecular mechanisms of synaptic specificity in C. elegans nerve ring
Daniel A. Colon-Ramos, Yale University

My lab is interested in understanding the developmental events that direct precise neural connectivity. In particular, we are interested in how these events are coordinated in complex neuropil structures such as the brain. How are these developmental events simultaneously coordinated between pre- and postsynaptic partners to allow precise wiring? How do they give rise to highly organized neuropil structures such as the brain?

We use the nematode C. elegans to look at the development of circuits in vivo and with single cell resolution. We recently showed that connectivity between two interneurons, AIY and RIA, in C. elegans is orchestrated by a pair of glial cells that express UNC-6 (netrin). In the postsynaptic neuron RIA, the netrin receptor UNC-40 (DCC, deleted in colorectal cancer) plays a conventional guidance role, directing outgrowth of the RIA process ventrally toward the glia. In the presynaptic neuron AIY, UNC-40 (DCC) plays an unexpected and previously uncharacterized role: It cell-autonomously promotes assembly of presynaptic terminals in the immediate vicinity of the glial cell endfeet. These results indicate that netrin can be used both for guidance and local synaptogenesis and suggest that glial cells can function as guideposts during the assembly of neural circuits in vivo.

These findings prompt the following questions: How does the Netrin receptor direct synapse formation? How do glial cells orchestrate circuit assembly in the brain? What other molecular signals govern synaptic targeting in the nematode brain? Our lab couples genetic, molecular and biochemical techniques to answer these questions and indentify the organizing principles that direct precise circuit connectivity in the nematode brain.

Cooperation Between Neuronal And Intestinal Protein Kinase D Isoforms Is Essential For Salt Taste Learning
Ya Fu, Albert Einstein College of Medicine

To ensure survival and optimize reproduction, C. elegans must accurately sense attractive environmental stimuli while avoiding toxins, predators and starvation. Consequently, C. elegans' behavior towards attractive chemosensory signals (e.g., Na+ ions) can be modified by associated cues (e.g., starvation) and previous experience. Behavioral plasticity, based on associative learning, is a conserved neurophysiological process, but knowledge of underlying signaling mechanisms is limited. Using molecular and classical genetics, in concert with biochemical analysis and a learning paradigm, we discovered that two protein kinase D (PKD) isoforms, DKF-2A and DKF-2B, are essential for salt taste induced plasticity.

Two promoters initiate transcription of the C. elegans dkf-2 gene. The processed mRNAs encode 2 PKD isoforms: DKF-2A is expressed in intestinal cells; DKF-2B accumulates in neurons comprising chemosensory circuitry. DKF-2A/2B and other PKDs constitute a special class of protein kinase C (PKC) effectors that generate novel branches in diacylglycerol (DAG)-controlled signaling networks. Activated PKDs translocate from plasma membrane to intracellular locations and phosphorylate effector proteins that are not PKC substrates.

In contrast to WT C. elegans, DKF-2 deficient animals are incapable of switching attraction to 25 mM Na+ to aversion after preincubation with 100 mM sodium acetate (minus food). Reconstitution of dkf-2(pr3) null animals with a dkf-2A::DKF-2A-GFP or dkf-2B::DKF-2B-GFP transgenes failed to restore Na+-induced learning. However, transgenic animals expressing DKF-2A-GFP and DKF-2B-GFP in intestine and neurons, respectively, were indistinguishable from WT C. elegans in behavioral plasticity. Thus, a Na+-induced behavioral change is triggered by a binary detector system that is embedded in nervous tissue and the gut. This implies that PKD-regulated behavioral output reflects integration of signaling information acquired by both neurons and intestinal cells.

The molecular basis for experience-dependent learning was clarified. EGL-8, a PLCα4 ortholog, produces DAG that controls PKC-mediated activation of DKF-2 isoforms, which in turn, triggers Na+-induced plasticity. TPA-1, a DAG activated PKCδ/θ homolog, exclusively controls in vivo activation (and functions) of DKF-2B in neurons and DKF-2A in intestine.

Functions of the EGL-8, DAG, TPA-1, DKF-2 signaling module are not limited to either plasticity or physiological outputs dependent on interactions between different cell types. The intestinal EGL-8-DAG-TPA-1-DKF-2A pathway independently promotes high-level induction of >75 mRNAs that mediate innate immunity in animals lacking DKF-2B. Conversely, neuronal DKF-2B mediates chemotaxis to volatile odorants in DKF-2A depleted C. elegans.

MicroRNAs as modulators of aging in a simple animal model
Carolina Ibanez-Ventoso, Rutgers University

A critical research priority in gerontology is to determine effective strategies that delay or block components of age-related decline, thereby extending the period of healthy, productive life. To meet the challenge of maximizing human healthspan, we will need to define the genes that influence the quality of aging and demonstrate how their manipulation can have therapeutic benefit. Given the existence of several "public" mechanisms of aging (those conserved across species), simple animal models have become important tools for elaborating the basic biology of aging. We exploit the considerable experimental advantages of the invertebrate animal Caenorhabditis elegans to address the roles of microRNAs in the aging process.

MicroRNAs (miRNAs) are ~22nt molecules that usually target cognate gene sequences to down-regulate translational expression. The first genetically identified miRNAs were the C. elegans lin-4 and let-7. High conservation of miRNA sequences as well as detection of large copy number of mir genes in a broad range of species have led to recent appreciation of miRNA regulation as a major control mechanism in cells. Indeed, miRNAs impact diverse cellular processes including cell proliferation, cell differentiation, cell death, cell signaling, stress response and metabolism. Due to the control of fundamental biological mechanisms, it is not unexpected that miRNAs are being associated to an increasing number of diseases including cancer, muscular dystrophy and neurodegenerative disorders.

To date, very few studies have addressed miRNA expression in mammalian aging per se. We have conducted the first genome-wide analysis of how miRNAs change with age in any organism (C. elegans) and identified that about half of the C. elegans miRNAs are age regulated. In addition, we predicted by computational analysis miRNA sites in the 3' UTRs of genes known to influence C. elegans lifespan and 3' UTRs of insulin genes (the insulin/IGF signaling pathway has an evolutionary conserved role in aging). The age-regulated expression as well as the potential regulation of gerontogenes and insulin genes suggests that miRNAs modulate the aging process. Indeed, C. elegans miRNA lin-4 does influence lifespan and the expression of healthspan indicators like age pigments. Since miRNAs are conserved (we defined in a recent sequence comparison survey that ~55% C. elegans miRNAs have homologous sequences in humans [6]), there is a strong likelihood that study of miRNA actions in C. elegans will influence future experimentation in mammalian aging research that tests for similar roles in higher organisms including humans.

Survival and death of Bacillus species in C. elegans
Maria-Halima Laaberki, Columbia University

Bacterial spores are resistant to a wide range of chemical and physical insults that are normally lethal for the vegetative form of the bacterium. While the integrity of the protein coat of the spore is crucial for spore survival in vitro, far less is known about how the coat provides protection in vivo against predation by ecologically relevant hosts. Assays had characterized the in vitro resistance of spores to peptidoglycan hydrolyzing enzymes like lysozyme that are also important effectors of innate immunity in a wide variety of hosts. Here, we use the bacteriovorous nematode Caenorhabditis elegans, a likely predator of Bacillus spores in the wild, to characterize the role of the spore coat in an ecologically relevant spore-host interaction. We found that ingested wild type B. Subtilis spores were resistant to worm digestion whereas vegetative forms of the bacterium were efficiently digested by the nematode. Using B. subtilis strains carrying mutations in spore coat genes, we observed a correlation between the degree of alteration of the spore coat assembly and the susceptibility to the worm degradation. Surprisingly, we found that the spores that were resistant to lysozyme in vitro can be sensitive to C. elegans digestion depending on the extent of the spore coat structure modifications. We further investigate the role and the transcriptional regulation of C. elegans lysozymes in this process. The genome of C. elegans presents 10 genes encoding for putative lysozyme-like proteins belonging to, at least, three families of lysozyme, with different substrate specificities. Notably, we found that the intestinal transcriptional regulator, Elt-2, is involved in the expression of lysozymes of C. elegans and that one lysozyme, Lys-4, is the main lysozyme active against Bacillus peptidoglycan.


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