Cilia are ubiquitous cellular organelles critical for many developmental and physiological processes, including olfaction. Cilia growth is likely under tight biological control since distinct cell types possess cilia with different numbers and lengths. However, little is known about what factors regulate cilia morphology and how morphology impacts function. This proposal aims to address fundamental questions about cilia structure and function using olfactory cilia as a model. Odor detection begins when odorants bind to odorant receptors (ORs) on the cilia of olfactory sensory neurons (OSNs) in the nose. The mouse main olfactory epithelium contains several million OSNs, each of which expresses one OR type out of a repertoire of ~1200. Therefore, a few thousand OSNs share the same OR identity. The proposed research is based on the intriguing discovery that OSNs expressing the same OR display location-dependent differences in cilia length. When subsets of OSNs are labeled with specific markers in the whole-mount olfactory epithelium, the cilia length is found to increase on average from ~2 ?m in the posterior to up to ~14 ?m in the anterior nasal septum. Remarkably, the cilia length pattern is positively correlated with odorant absorption in the nasal cavity, and OSNs with longer cilia are more sensitive to odorant stimulation. Sensory experience and neuronal activity are not required for the establishment and maintenance of the cilia pattern, but ACIII, a key olfactory signaling molecule and generic marker for primary cilia, is essential in this process. The goal of this proposal is to investigate what factors shape olfactory cilia and how cell location and cilia length impact the function of OSNs using immunohistochemical, genetic, and electrophysiological tools. In this proposal, I will test two hypotheses. First, olfactory signaling components play novel and critical roles in shaping cilia length, independent of odor-induced activity (Aim 1). Second, OSNs with long and short cilia have distinct roles in processing odor information depending on the type of stimulation they encounter (Aim 2). The results will offer new insights into the structure and function of sensory cilia and the coding and processing of odor information.
This proposal will explore the physiological mechanisms underlying the structure and function of cilia, ubiquitous cellular organelles critical for many biological processes, including sensory perception. Defects in cilia cause human diseases involving anosmia, blindness, obesity, cystic kidney disorder, and brain malformation. This work will provide novel insights into the regulation of cilia growth and function and will contribute to the development of treatments for cilia-related disorders.
|Challis, Rosemary C; Tian, Huikai; Yin, Wenbin et al. (2016) Genetic Ablation of Type III Adenylyl Cyclase Exerts Region-Specific Effects on Cilia Architecture in the Mouse Nose. PLoS One 11:e0150638|
|Challis, Rosemary C; Tian, Huikai; Wang, Jue et al. (2015) An Olfactory Cilia Pattern in the Mammalian Nose Ensures High Sensitivity to Odors. Curr Biol 25:2503-12|