Molecular Genesis and Organization of Olfactory Transduction Components and Cilia

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DESCRIPTION (provided by applicant): The mammalian olfactory system achieves remarkable sensitivity through novel genetic mechanisms, cellular specializations, and subsequent processing of sensory information by neuronal circuitry. The earliest steps in the transduction of odorant information into signals that are propagated to the brain occur in olfactory cilia. The dozen long immotile cilia of each olfactory neuron are the only part of the sensory cell exposed to the outside environment and the sources of odorant stimuli and their existence is essential for efficient odor detection. The olfactory neuron has developed efficient but poorly understood mechanisms for enriching the components of olfactory transduction (odorant receptor (OR), G protein (Golf), adenylyl cyclase (AC3) and olfactory cyclic nucleotide channel) in cilia. The abundant expression of the single polypeptide comprising the AC3 enzyme in all olfactory neurons makes it particularly amenable to elucidate the pathways and mechanisms responsible for cilia localization and enrichment. In this grant we will use molecular and genetic approaches to investigate the hypothesis that a specialized but broadly utilized mechanism and pathway is responsible for AC3 localization to cilia and that this localization is critical for cilia dynamics and function. In specific aim 1, we target the cilia localization signa of AC3 in vivo by a conditional genetic disruption approach and determine the consequences of re- localization of AC3 into different cellular compartments. In specific aim 2, we will utilize a robut expression system to identify components of the AC3 translocation/enrichment pathway leading to cilia localization and examine the dynamics of AC3 in cilia and role of AC3 localization in modulation of cilia length. Together, these experiments will expand our understanding of how an important class of proteins are enriched in cilia and the importance of their selective localizatio to this organelle. Cilia are present in essentially all terminally differentiated mammalian cells ad critical for the development of the organism. The pathways and mechanisms underlying adenylyl cyclase localization will have important consequences for olfaction, sensory communication and broadly for human health and understanding disease. The abundance of AC3 in olfactory neurons makes it particularly amenable for detailed studies. The AC3 enzyme is broadly expressed and highly enriched in many neuronal cilia of the brain and kidney where it likely mediates neuroendocrine/neurotransmitter signaling and its subcellular localization in these cells appear to be mediated by similar mechanisms. Modulation of this pathway should perturb complex behaviors and metabolic processes. Additionally, it is likely that the cilia localization pathway utilized by AC3 is shared by other proteins whose presence in cilia is critical for cellular function. Elucidation of these pathways will provide insight into cellular processes that have widespread consequences for human health.