Mechanisms of sensory neuron morphological diversification, signaling, and functional plasticity

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PROJECT SUMMARY The overall goal of NIGMS-funded research in my lab is to describe the molecular and cellular mechanisms by which individual sensory neuron types acquire their distinctive morphologies and functions, and explore how these properties are further shaped by the animal's experience and environment. In one area, we investigate how sensory neurons in C. elegans elaborate cell type-specific cilia, organelles that house sensory signaling molecules. In a second area, we characterize the mechanisms by which C. elegans exhibits highly sensitive and experience-dependent responses to environmental temperature, a critical but poorly understood sensory modality. These issues are interdependent; neuronal anatomy governs neuronal function, and conversely, neuronal activity shapes neuronal morphology. Integrating these projects will not only allow us to continue our ongoing successful research strategies, but will also enable us to initiate novel avenues of investigation. A first major goal for the next several years is to develop a detailed understanding of the genetic pathways by which ciliary morphological diversity is achieved. Structurally unique cilia are critical for the functions of specific sensory neuron types in multiple species. Although ciliogenic mechanisms are now well-described, how diversity in ciliary structures is generated is unclear. We plan to analyze mechanisms generating ciliary morphological diversity in C. elegans, and also expand our analysis to mammalian cells. A second major goal is to dissect the properties of a class of novel but conserved thermosensory molecules that we recently described, and to explore how these proteins contribute to the extraordinary experience-dependent thermosensitivity of a sensory neuron type. We will also examine how transcriptional and translational changes in single thermosensory neuron types contribute to state- and experience-dependent plasticity in neuronal and circuit properties to alter thermosensory behaviors. A particularly innovative goal is to combine our expertise in neuronal cell biology and analysis of stimulus-evoked sensory responses to systematically describe how sensory activity modulates cilia protein composition and neuronal function, and conversely, explore how cilia architecture dictates sensory neuron response profiles. Under this combined award, we will be able to employ our multifaceted experimental approach to broaden and deepen our analysis of neuronal form and function, incorporate conceptual and experimental innovations to establish new research directions, and provide a more integrative research training experience. Defects in cilia structure and function, as well as altered neuronal signaling and plasticity, underlie a plethora of neurological disorders. Given the extensive conservation of ciliogenic as well as neuronal pathways between mammals and C. elegans, we fully expect that findings from this work will influence and guide related investigations in other organisms in both development and disease.