Molecular and functional anatomy of the mouse olfactory epithelium

Sammanfattning: The olfactory system is important for social behaviors, feeding and avoiding predators. Detection of odorous molecules is made by odorant receptors on specialized sensory neurons in the olfactory epithelial sheet. The olfactory sensory neurons are organized into a few regions or “zones” based on the spatially limited expression of odorant receptors. In this thesis the zonal division and functional specificity of olfactory sensory neurons have been studied in the mouse. We find that zones 2-4 show overlapping expression of odorant receptors while the border between the regions that express a zone 1 and a zone 2 odorant receptor, respectively, is sharp. This result indicates that zone 1 and zones 2-4 are inherently different from each other. In cDNA screens, aimed at finding genes whose expression correlate to the zonal expression pattern of odorant receptors, we have identified a number of signaling proteins implicated in neural-tissue organogenesis in other systems. The differential expression pattern of identified genes suggests that regional organization is maintained during the continuous neurogenesis in the olfactory epithelium as a result of counter gradients of positional information. We show that the gene c-fos is induced in olfactory sensory neurons as a result of cell activation by odorant exposure. A zonal and scattered distribution of c-Fos-positive neurons resembled the pattern of odorant receptor expression and a change of odorant results in a switch in which zone that is activated. Whereas earlier studies suggest that the odorant receptors are relatively broadly tuned with regard to ligand specificity, the restricted patterns of c-Fos induction suggests that low concentrations of odorous molecules activate only one or a few ORs. Studies on olfactory detection abilities of mice with zonal-restricted lesions in the olfactory epithelium show that loss of a zone has severe effects on the detection of some odorants but not others. These findings lend support to a hypothesis that odorant receptors are tuned to more limited numbers of odorants. Regional differences in gene expression and differences in response to toxic compounds between the zones indicate that there may be differences in tissue homeostasis within the epithelium. We have found that there are differences in proliferation and survival of olfactory sensory neurons in regions correlating to receptor expression zones. Identified differences with regard to gene expression, tissue homeostasis and odorant detection show that the olfactory epithelium is divided into regions that transduce different stimulus features.