Final Report Summary - OLFACTORYIGLURS (Olfactory perception in Drosophila: analysis of a novel iGluR-related family of odorant receptors)
The overall goal of our research is to understand how sensory information in the environment is detected and processed in the brain to evoke an appropriate behavioural response. We focus on the olfactory system of the fruit fly, Drosophila melanogaster, a model genetic organism that displays a sophisticated repertoire of odour-driven behaviours under the control of neural circuits that have similar anatomical and functional properties to those of mammals but with significantly reduced complexity. We aim to gain insights into both a fundamental problem of neuroscience - how genes and circuits control behaviour. Our work also has potential direct application in the development of novel strategies to control the olfactory behaviours of pest insects. Our ERC project focused on a novel family of Drosophila olfactory receptors called the Ionotropic Receptors (IRs). IRs are structurally related to ionotropic glutamate receptors (iGluRs), a conserved class of ligand-gated ion channel that are best characterised for their roles in synaptic communication in vertebrate nervous systems. We used the IRs as a model system to study several aspects of the function and evolution of olfactory receptors and the neural circuits in which they are expressed.
Emergence and divergence of the IRs: by comprehensive evolutionary genomics and in situ expression analysis we have shown that IRs are expressed in olfactory organs across Protostomia - a major branch of the animal kingdom that encompasses arthropods, nematodes, and molluscs - indicating that they represent an ancestral protostome chemosensory receptor family. We distinguished two subfamilies of IRs: conserved “antennal IRs”, which are likely to define the first olfactory receptor family of insects, and species-specific “divergent IRs”, which are expressed in peripheral and internal gustatory neurons, implicating this family also in taste sensing.
Molecular architecture of IRs: to elucidate how these peripheral chemosensors have evolved mechanistically from synaptic iGluRs, we combined in vivo and in vitro physiological and cell imaging approaches. We found that IRs act in likely heterotetrameric complexes of up to three subunits, comprising individual ligand-specific receptors and one or two broadly expressed coreceptors. Heteromeric IR complex formation is necessary and sufficient for trafficking to chemosensory cilia in vivo and mediating ligand-evoked electrophysiological responses in heterologous cells. Structure-function analysis has begun to reveal the role of different subunits and protein domains in subcellular trafficking, odour ligand recognition and ion conduction. Our findings provide insights into the conserved and distinct architecture of these olfactory receptors and their synaptic ion channel ancestors. Moreover, they offer perspectives into the use of IRs as a novel type of custom-designed chemoreceptor. Such sensors could offer invaluable practical tools, for example, in pollutant detection or clinical diagnosis.
Structure and function of IR neural circuits: we have performed electrophysiological screens to identify ligands for IRs and generated genetic reagents to visualise the organisation and activity of the IR neural circuits. These efforts have allowed us to determine how chemical stimuli detected by IRs are represented in spatial and temporal patterns of neural activity in the brain. Moreover, this analysis has permitted comparison of the properties of the IR chemosensory systems with those of sensory circuits expressing other classes of chemosensory receptors, and therefore insights into the driving forces and mechanisms underlying their development and evolution. Finally, by manipulating the function of individual IR sensory pathways, we also defined the specific innate behaviours these chemosensory circuits control, including those mediating attraction and aversion, as well as those controlling social behaviours such as courtship.
Emergence and divergence of the IRs: by comprehensive evolutionary genomics and in situ expression analysis we have shown that IRs are expressed in olfactory organs across Protostomia - a major branch of the animal kingdom that encompasses arthropods, nematodes, and molluscs - indicating that they represent an ancestral protostome chemosensory receptor family. We distinguished two subfamilies of IRs: conserved “antennal IRs”, which are likely to define the first olfactory receptor family of insects, and species-specific “divergent IRs”, which are expressed in peripheral and internal gustatory neurons, implicating this family also in taste sensing.
Molecular architecture of IRs: to elucidate how these peripheral chemosensors have evolved mechanistically from synaptic iGluRs, we combined in vivo and in vitro physiological and cell imaging approaches. We found that IRs act in likely heterotetrameric complexes of up to three subunits, comprising individual ligand-specific receptors and one or two broadly expressed coreceptors. Heteromeric IR complex formation is necessary and sufficient for trafficking to chemosensory cilia in vivo and mediating ligand-evoked electrophysiological responses in heterologous cells. Structure-function analysis has begun to reveal the role of different subunits and protein domains in subcellular trafficking, odour ligand recognition and ion conduction. Our findings provide insights into the conserved and distinct architecture of these olfactory receptors and their synaptic ion channel ancestors. Moreover, they offer perspectives into the use of IRs as a novel type of custom-designed chemoreceptor. Such sensors could offer invaluable practical tools, for example, in pollutant detection or clinical diagnosis.
Structure and function of IR neural circuits: we have performed electrophysiological screens to identify ligands for IRs and generated genetic reagents to visualise the organisation and activity of the IR neural circuits. These efforts have allowed us to determine how chemical stimuli detected by IRs are represented in spatial and temporal patterns of neural activity in the brain. Moreover, this analysis has permitted comparison of the properties of the IR chemosensory systems with those of sensory circuits expressing other classes of chemosensory receptors, and therefore insights into the driving forces and mechanisms underlying their development and evolution. Finally, by manipulating the function of individual IR sensory pathways, we also defined the specific innate behaviours these chemosensory circuits control, including those mediating attraction and aversion, as well as those controlling social behaviours such as courtship.