The remarkable sensitivity and specificity of mammalian olfaction arises from the contributions at the molecular, cellular and tissue levels to establish a sensory organ. One of the most important components in this developmental process is the olfactory receptor (OR) protein. This large family of related GPCR coupled receptors is primarily responsible for defining the range of odorants that can be detected by an organism. The observation that each olfactory neuron expresses a single type of OR has important implications for information coding. Namely, the consequences of a ligand/OR interaction with a single receptor type can be directly translated into the physiological signal that the cell propagates to the olfactory bulb at the front of the brain. Additionally, the segregation of the axonal inputs into the olfactory bulb, organized according to the OR that each cell expresses, extends this relationship such that each discrete glomeruli represents an information unit reporting whether volatiles are present in the environment. Although extensive further processing of this initial signal by the olfactory bulb and higher brain areas is required to generate the complex perception and identification of odors associated with mammalian olfaction, the selective expression of exactly one OR in each mature olfactory neuron is critical for accurate information flow in this sensory system. In the absence of this highly regulated expression mechanism, the response profile of olfactory receptor neurons (ORNs) and the accurate organization of their projections to the olfactory bulb would be severely compromised. In spite of the critical importance of OR gene regulation, we know surprisingly little about the events associated with OR choice and regulation in olfactory function In this proposal, we will define the key steps utilized by olfactory receptor neurons to generate the selective expression of a single olfactory receptor protein type in each mature sensory neuron. These experiments will afford new insights into one of the most critical events in the establishment of a functional olfactory system and elucidate the role of specific regulatory proteins in this process. In addition, the regulation of the mammalian olfactory receptors provides a valuable paradigm for monoallelic gene expression that is critical for the proper expression of several genes that contribute to normal health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC008295-04
Application #
7860335
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Davis, Barry
Project Start
2007-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$340,531
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sharma, Tanu; Reed, Randall R (2013) Balancing survival: the role of CTGF in controlling experience-modulated olfactory circuitry. Neuron 79:1037-9
Bermingham-McDonogh, Olivia; Corwin, Jeffrey T; Hauswirth, William W et al. (2012) Regenerative medicine for the special senses: restoring the inputs. J Neurosci 32:14053-7
McIntyre, Jeremy C; Davis, Erica E; Joiner, Ariell et al. (2012) Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model. Nat Med 18:1423-8
Roby, Yang A; Bushey, Michael A; Cheng, Li E et al. (2012) Zfp423/OAZ mutation reveals the importance of Olf/EBF transcription activity in olfactory neuronal maturation. J Neurosci 32:13679-88a
Tadenev, Abigail L D; Kulaga, Heather M; May-Simera, Helen L et al. (2011) Loss of Bardet-Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targeting. Proc Natl Acad Sci U S A 108:10320-5
Bennett, Mosi K; Kulaga, Heather M; Reed, Randall R (2010) Odor-evoked gene regulation and visualization in olfactory receptor neurons. Mol Cell Neurosci 43:353-62
Lane, Andrew P; Turner, Justin; May, Lindsey et al. (2010) A genetic model of chronic rhinosinusitis-associated olfactory inflammation reveals reversible functional impairment and dramatic neuroepithelial reorganization. J Neurosci 30:2324-9
Gupta, Rana K; Arany, Zoltan; Seale, Patrick et al. (2010) Transcriptional control of preadipocyte determination by Zfp423. Nature 464:619-23
Kim, Euiseok J; Leung, Cheuk T; Reed, Randall R et al. (2007) In vivo analysis of Ascl1 defined progenitors reveals distinct developmental dynamics during adult neurogenesis and gliogenesis. J Neurosci 27:12764-74
Leinders-Zufall, Trese; Cockerham, Renee E; Michalakis, Stylianos et al. (2007) Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium. Proc Natl Acad Sci U S A 104:14507-12

Showing the most recent 10 out of 12 publications