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Olfactory Receptor Accessory Proteins Play Crucial Roles in Receptor Function And Olfactory Receptor Accessory Proteins Play Crucial Roles in Receptor Function and Gene Choice by Ruchira Sharma Department of Molecular Genetics and Microbiology Duke University Date:_______________________ Approved: ___________________________ Hiroaki Matsunami, Supervisor ___________________________ Debra Silver ___________________________ Nina Sherwood ___________________________ Richard Mooney ___________________________ William Wetsel Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Molecular Genetics and Microbiology in the Graduate School of Duke University 2017 ABSTRACT Olfactory Receptor Accessory Proteins Play Crucial Roles in Receptor Function and Gene Choice by Ruchira Sharma Department of Department of Molecular Genetics and Microbiology Duke University Date:_______________________ Approved: ___________________________ Hiroaki Matsunami, Supervisor ___________________________ Debra Silver ___________________________ Nina Sherwood ___________________________ Richard Mooney ___________________________ William Wetsel An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Molecular Genetics and Microbiology in the Graduate School of Duke University 2017 Copyright by Ruchira Sharma 2017 Abstract Understanding how we detect our environment is crucial to understanding how life evolved and now functions. Volatile chemicals from our surroundings are sensed by our olfactory system, a primitive sense that organisms have relied on for survival for millions of years. Mammals express a large family of odorant receptor (OR) genes in the sensory neurons in the nose that mediate this chemosensation. Each mature olfactory sensory neuron (OSN) expresses a single allele of a single OR gene at one time although in the absence of a functional gene OSNs can switch to another OR gene. A functional OR can inhibit the expression of another OR by co-opting the unfolded protein response (UPR). How OSNs make their initial OR gene choice and the mechanisms by which the ORs interact with UPR factors remain unknown. In this study, I make use of a mouse that has both RTP1 and RTP2 knocked out while keeping the intervening sequence intact. These proteins are required for the efficient surface trafficking of ORs in heterologous cells and the double knock-out mouse could be used to study the gene regulation of OSNs during a large-scale perturbation of the trafficking of ORs to the cell surface. We initially generate and validate the RTP1 and RTP2 double knock out mouse (RTP1,2DKO) and show that consistent with our heterologous expression system, the mutant mice have OR trafficking defects. These OR trafficking defects give rise to higher rates of cell death and the mutant mice have fewer iv mature OSNs. Surprisingly we identified a subset of ORs that were overrepresented in the RTP1,2DKO animals. Some of these ORs can target the cell surface in the absence of the RTPs. This finding gave rise to two cohorts of ORs, those that are underrepresented in the mutants and presumably dependent on the RTPs for cell surface trafficking and ORs that are overrepresented in RTP1,2DKO. Previous studies have shown that OSNs co-opt the unfolded protein response (UPR) to stabilize OR gene choice of a functional OR. We show that OSNs expressing underrepresented receptors were more likely to be unable to terminate UPR and had a higher tendency to switch the OR it was initially expressing. Using these two cohorts we showed that the trafficking of ORs to the cell surface is a crucial step in the stabilization of the expression of the OR. In the absence of this cell surface trafficking the OSN is unable to terminate the UPR pathway and either undergoes cell death or OR gene switching. v Dedication To Amma for pushing and Daddy for worrying. vi Contents Abstract .......................................................................................................................................... iv List of Tables ................................................................................................................................ xii List of Figures ............................................................................................................................. xiii Acknowledgements ................................................................................................................... xvi 1. Introduction ............................................................................................................................... 1 1.1 Mammalian olfactory system ......................................................................................... 2 1.2 Mammalian olfactory receptors ..................................................................................... 4 1.2.1 Canonical odorant receptor signaling ...................................................................... 5 1.2.2 Multiple signaling pathways observed in OSNs .................................................... 7 1.2.3 Desensitization and adaptation ................................................................................. 8 1.3 OR gene expression .......................................................................................................... 9 1.3.1 All OR genes are silenced by default ...................................................................... 11 1.3.2 A single OR gene is chosen for expression ............................................................ 11 1.3.3 Immature OSNs contain transcripts from multiple OR genes ........................... 13 1.3.4 Negative feedback loop ............................................................................................ 13 1.3.5 OSNs co-opt the unfolded protein response (UPR) pathway to stabilize OR gene choice .......................................................................................................................... 14 1.4 Axon targeting ................................................................................................................ 17 1.4.1. ORs play a pivotal role in axon targeting ............................................................. 17 1.4.2 The region where an OR is expressed in the OE determines the position of its glomerulus ........................................................................................................................... 18 vii 1.4.3 The number of OSNs expressing an OR is correlated to the size of the glomerulus ........................................................................................................................... 19 1.5 Odor coding .................................................................................................................... 20 1.6 Cell surface trafficking of ORs ...................................................................................... 21 1.6.1 RTP1 and RTP2 .......................................................................................................... 22 2. RTP1 and RTP2 double knock-out mice show defects in their olfactory system .......... 24 2.1 Introduction ..................................................................................................................... 24 2.2 Results .............................................................................................................................. 25 2.2.1 Generation of RTP1,2DKO mice .............................................................................. 25 2.2.2 RTP1,2DKO OSNs show defects in OR trafficking .............................................. 27 2.2.3 RTP1,2DKO mice have fewer mature sensory neurons ...................................... 28 2.2.4 Odorant evoked electrophysiological responses in RTP1,2DKO mice are diminished ........................................................................................................................... 32 2.2.5 RTP1,2DKO can detect odorants ............................................................................. 33 2.2.6 RTP1,2DKO show mating depression .................................................................... 34 2.3 Conclusions ..................................................................................................................... 35 3. RTP1,2DKO mice express a biased OR repertoire ............................................................. 37 3.1 Introduction ..................................................................................................................... 37 3.2 Results .............................................................................................................................. 37 3.2.1 RNA-seq gene expression analysis on the RTP1,2DKO OE ................................ 37 3.2.2 OR are one of the most differentially expressed gene families .......................... 39 3.2.3 The proportion of OSNs expressing oORs increases in older RTP1,2DKO mice ............................................................................................................................................... 44 viii 3.2.4 Underrepresentation or overrepresentation cannot be predicted using sequence similarity ............................................................................................................. 46 3.2.5 Protein sequence determines whether an OR is underrepresented or overrepresented .................................................................................................................
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