Odorant receptors: mechanisms of gene expression and signal transduction

Abstract

Odorants activate odorant receptors (ORs) that are present in the cilia of the olfactory sensory neurons. Odorant receptors are G protein coupled receptors (GPCRs) and belong to a large family composed of approximately 1000 genes in the mouse, and 400 genes in humans. In this project, we aim to analyze two different aspects related to the function of these receptors: (1) Each olfactory sensory neuron expresses one allele of a single gene out of the ~ 1000 OR genes (the so called 'one neuron one receptor rule'). Olfactory neurons show a singular nuclear architecture, which seems to be required for odorant receptor gene regulation. We plan to analyze the role played by specific histone marks (such as H3K27me3) and non-coding RNAs in the spatial organization of the odorant receptor genes in the nucleus. (2) During odorant signal transduction, odorant receptors couple to an olfactory specific Galpha protein, denominated Galphaolf. We have shown that Ric-8B acts as a GEF (GTP exchange factor) on Galphaolf in vitro. Analysis of knockout mice showed that the Ric-8B gene is essential for embryogenesis, and that knockout embryos show reduced mTOR function. We plan to investigate the molecular mechanisms involved in the regulation of mTOR function by Ric-8B. We have also produced a tissue (olfactory epithelium) specific knockout for Ric-8B. Recent experiments have shown that olfactory sensory neurons from these mice do not express the Galphaolf protein, and die more frequently. We plan now to examine the molecular mechanisms that lead to such a phenotype. (AU)