Damien O'Halloran

In my lab we use the invertebrate nematode, Caenorhabditis elegans, to understand how animals detect and encode sensory information. By using the more compact C. elegans nervous system to address these questions we can leverage powerful genetic tools and anatomical datasets to dissect these problems. In C. elegans, a pair of olfactory sensory neurons (OSNs) termed the AWC, enable the animal to detect diverse attractive volatile odorants. Sustained presentation of these odors will result in decreased attraction to the exposed odor, and this change in sensitivity is termed adaptation. A protein kinase G (PKG) called EGL-4 is necessary for adaptation in the AWC neurons, and we have found that the secondary messenger, cGMP, slowly changes the sensory capacity of AWC by triggering the nuclear entry of EGL-4¹. We have also demonstrated that constitutively nuclear EGL-4 is required in the AWB neurons (another pair of olfactory neurons) for the detection of repellent odors, and that the Go alpha subunit protein GOA-1 regulates the nuclear localization of EGL-4 in both AWB and AWC neurons². More recently, we have discovered that the cyclic nucleotide gated (CNG) channel subunit, CNG-3, is necessary for short-term adaptation (lasting ~30mins) in the AWC and not required for long-term adaptation in AWC^3,4. Using biomolecular fluorescent complementation (BiFC) assays and electrophysiology we provided novel in vivo evidence that CNG-3 can complex with two other CNG channel subunits in the AWC OSNs to alter channel gating kinetics and cGMP sensitivity⁴.

^{Figure 1. Model of PKG activity in AWB and AWC to shape sensory behavior. In the AWC primary sensory neuron pair, EGL-4 is localized to the cytosol and translocates to the nucleus after sustained odor exposure. This nuclear translocation event is dependent on the Goα subunit protein GOA-1. In the AWB primary sensory neuron pair, EGL-4 is constitutively localized to the nucleus, and this nuclear localization of EGL-4 is necessary for normal AWB dependent responses and is dependent on GOA-1.}

My lab is also using a comparative approach to investigate how other nematodes that have a parasitic lifestyle (unlike C. elegans, which is free-living) detect their specific hosts. For these studies we use the insect parasitic nematode Heterorhabditis bacteriophora and intestinal blood-feeding species of hookworm to study sensory behavior using comparative genomics in order to uncover sensory transduction molecules that enable nematodes to identify their host and begin parasitic development. We have recently developed a database of nematode chemoreceptors which are critical receptors that form substrates for host specific cues^5,6.

^{Figure 2. From the home page of NemChR-DB users can navigate various links at the top to browse the database (circle 1), search and download results (circle 2 and 3), or explore functional annotations as well as related literature (circle 4). Users can also characterize candidate nematode chemoreceptors using TM Finder to identify and visualize predicted transmembrane domains (circle 5) or query the database using BlastP to uncover related sequences (circle 6). NemChR-DB can be accessed at the following site: http://ohalloranlab.net/nemchr-db}

This branch of research within my lab is important as parasitic nematodes constitute one of the major threats to human health by causing diseases of major socioeconomic importance. Recent estimates indicate more than 1 billion people are infected with parasitic nematodes, and more than a dozen species routinely parasitize humans. In collaboration with the Eleftherianos and Hawdon labs, we have recently developed genetic tools for gene silencing in H. bacteriophora^7,8 and also identified secreted virulence factors that enable H. bacteriophora to infect and evade its host’s immune response^9,10,11,12. These experiments require both computational and experimental approaches to understand nematode parasitism.

^{Figure 3. RNAi mediated phenotype and transcript changes in H. bacteriophora injected with dpy-13 dsRNA. Adult H. bacteriophora hermaphrodites that were injected with dpy-13 dsRNA produced progeny with dumpy phenotype.}

Lab Website: www.ohalloranlab.net