Converting stochastic olfactory receptor expression to stereotypic axon guidance programs

总结

Summary The mammalian olfactory system has the remarkable ability to detect and identify an astronomical number of volatile chemicals, termed odorants. Odorants are detected by olfactory receptors (ORs) at the cilia of olfactory sensory neurons (OSNs), which transform chemical information into electrical signals transmitted to the olfactory bulb (OB). Each one of the ~1000 OR genes is expressed in a monogenic, monoallelic, and seemingly stochastic fashion in the main olfactory epithelium (MOE), yet axons from OSNs with the same OR converge to distinct and stereotypic neuropil structures at the OB called glomeruli. Because each OR identity is represented by corresponding glomeruli, odor binding to distinct OR repertoires activates an odor-specific combination of glomeruli, providing the basis of odor perception. Here, we investigate molecular mechanisms that transform the random expression of a single OR in the MOE to stereotypic and highly coordinated axon targeting programs in the OB. Previous work revealed that the OR sequence plays an essential regulatory function in this axon guidance process, in part, by directing the expression programs of genes involved in axon guidance and cell adhesion. We reveal that the OR identity may inform this process by eliciting distinct levels of endoplasmic reticulum (ER) stress, which in turn, influence transcriptional programs controlling axon targeting specificity. With the generation of a translational fluorescent reporter that quantifies the levels of ER stress-induced Perk signaling, we demonstrate that OSNs have distinct levels of ER stress according to the identity of the OR they express. Furthermore, by deconvoluting transcriptional networks, we identified transcription factors that transform ER stress levels into distinct axon guidance outputs. Based on these preliminary findings, we propose experiments that will decipher the function of ER stress-responsive transcription factors and will identify extracellular barcodes corresponding to various levels of ER stress. Moreover, we propose experiments that will untangle the contribution of OR identity and OSN origin to the cellular levels of ER stress and will identify OR protein sequences with a major role in this process. Our experiments promise to provide novel insight into a fascinating problem that has remained poorly understood for decades. Moreover, this work will uncover generalizable mechanisms responsible for converting cellular and molecular identity of neurons into precise axon guidance specificity, with immense basic and translational ramifications.