UCSF

Each olfactory sensory neuron (OSN) expresses exactly one olfactory receptor (OR) gene, a feature which requires both a limiting or inefficient process of OR transcriptional activation and a subsequent process of OR feedback. Monogenic expression of ORs is thought to underlie the ability of animals to sensitively and specifically identify innumerable cues, and therefore understanding how olfactory receptor genes are transcriptionally activated and how they elicit feedback are problems of paramount importance in understanding the development of the olfactory system. The thesis project presented herein demonstrates that OR feedback is elicited through a surprising ability of olfactory receptor protein to elicit the unfolded protein response (UPR), a ubiquitous and highly-conserved proteostatic signaling pathway that is typically thought to be responsive to stress conditions. Activation of the UPR by OR expression in OSNs drives translation of a transcription factor specific to chemosensory neurons, resulting in stabilization of OR choice and monogenic OR expression, OSN maturation, and a termination of further OR choice. This signaling pathway is general to vomeronasal sensory neurons (VSNs) and is most likely also found in other sensory cells with limited patters of G protein-coupled receptor expression including neurons of the trigeminal ganglion and the taste receptor cells of the tongue. Finally, the means by which ORs and vomeronasal receptors (VRs) activate the UPR is shown, with ORs and VRs activating the UPR indirectly and directly, respectively. Thus, while these receptors have divergent mechanisms of UPR activation, they have a convergent use of the UPR in order to coordinate monogenic receptor expression and to time development to the appearance of the chemoreceptor.