Cilia, microtubule-based protrusions from the cell surface, are cellular organelles present in nearly all mammalian cells. By converting environmental signals into intracellular responses, cilia serve many critical functions including perception of smell. Recent years have witnessed rapid progress in understanding the cell biology and signal transduction events in the cilia of various cell types. However, little is know about what factors shape cilia morphology and how the morphology impacts the function of cilia. We recently discovered that olfactory cilia vary drastically in length and consequently in physiological signals. Prompted by this novel finding, we aim to address these issues using the olfactory system as a model. Odor detection starts with the binding of odorants to specific odorant receptors (ORs) located in the cilia of olfactory sensory neurons (OSNs) in the nose. The mouse olfactory epithelium harbors several million OSNs, each of which expresses one type of OR out of a repertoire of ~1200. Therefore, a few thousand OSNs express any given OR. These neurons are scattered in one of a few broadly-defined zones in the olfactory epithelium, but their axons converge typically onto two discrete glomeruli in the olfactory bulb. Contrary to the common belief that mature OSNs have rather homogeneous morphology, we found that OSNs expressing the same OR significantly differ in cilia length. From the posterior to the anterior nasal septum, the cilia length gradually increases from ~1 mm to ~20 mm with the longest cilia (~50 mm) found in the dorsal recess. Remarkably, the heatmap of the cilia length roughly matches the odorant absorption pattern in the nasal cavity, as determined by airflow rate and odorant solubility. Prompted by this novel finding, this proposal aims to address several key issues regarding the structure, function, and modulation of OSN cilia by combining immunostaining, electrophysiological, genetic and computational approaches. Specifically, three hypotheses will be tested. First, the cilia length of OSNs is positively correlated with the odorant absorption pattern in the nasal cavity. Second, the cilia length of OSNs can be increased by enhanced sensory inputs and/or neuronal activity. Third, OSNs expressing the same OR but with different cilia morphology carry non-redundant information into the brain. The results will offer new insights into the structure and function of sensory cilia and advance our understanding of the coding and processing of odor information by the olfactory system.
This proposal will provide new insights into the structure, function and modulation of cilia, a cellular organelle present in nearly all cell types throughout the body and brain. Disruption of cilia leads to a variety of human diseases including anosmia, blindness, cystic kidney disorder, brain malformation, obesity, and cognitive deficits. Understanding the mechanisms underlying the growth of cilia will help to develop therapeutic means to restore the morphology and function of cilia under these pathological conditions.
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