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Molecular and functional anatomy of the mouse olfactory epithelium
Umeå University, Faculty of Medicine, Molecular Biology.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Molekylärbiologi , 2006. , 71 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1047
Keyword [en]
olfactory epithelium, odorant receptor, zone, odorant, gene expression, cell specification, c-Fos, dichlobenil, olfactometry, proliferation
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-868ISBN: 91-7264-138-X (print)OAI: oai:DiVA.org:umu-868DiVA: diva2:144807
Public defence
2006-10-06, Major Groove, 6L, Umeå Universitet, 901 87 Umeå, 09:30 (English)
Opponent
Supervisors
Available from: 2006-09-19 Created: 2006-09-19 Last updated: 2009-10-30Bibliographically approved
List of papers
1. Evidence for gradients of gene expression correlating with zonal topography of the olfactory sensory map
Open this publication in new window or tab >>Evidence for gradients of gene expression correlating with zonal topography of the olfactory sensory map
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2001 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 18, no 3, 283-295 p.Article in journal (Refereed) Published
Abstract [en]

Signals regulating diversification of olfactory sensory neurons to express odorant receptors and other genes necessary for correct assembly of the olfactory sensory map persist in the olfactory epithelium of adult mouse. We have screened for genes with an expression pattern correlating with the topography odorant receptor-expression zones. The Msx1 homeobox gene and a semaphorin receptor (Neuropilin-2) showed graded expression patterns in the olfactory epithelium. The gradients of Msx1 and Neuropilin-2 expression in basal cells and neurons, respectively, correlated with expression of a retinoic acid-synthesizing enzyme (RALDH2) in lamina propria. A BMP-type I receptor (Alk6) showed a reverse gradient of expression in the supporting cells of the epithelium. Considering known functions of identified genes in cell specification and axon guidance this suggests that zonal division of the olfactory sensory map is maintained, during continuous neurogenesis, as a consequence of topographic counter gradients of positional information. Copyright 2001 Academic Press.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-5321 (URN)10.1006/mcne.2001.1019 (DOI)11591129 (PubMedID)
Available from: 2006-09-19 Created: 2006-09-19 Last updated: 2010-04-20Bibliographically approved
2. Odorant-dependent, spatially restricted induction of c-fos in the olfactory epithelium of the mouse.
Open this publication in new window or tab >>Odorant-dependent, spatially restricted induction of c-fos in the olfactory epithelium of the mouse.
2005 (English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 96, no 6, 1594-602 p.Article in journal (Refereed) Published
Abstract [en]

Volatile odorous chemicals are detected by around a thousand different G protein-coupled odorant receptors in the mouse. We demonstrated that exposure of the behaving mouse to odorant for a few minutes led to induction of the immediate early gene c-fos for several hours in a fraction of the olfactory sensory neurones in the nasal cavity. Associated with this odorant-specific induction event was activation of extracellular-regulated kinase (ERK)1/2 that preceded increased c-fos expression. The distribution of odorant-activated neurones mimicked the scattered and spatially limited distribution of neurones expressing a single odorant receptor gene. A small change in odorant chemical structure caused a zonal shift in the spatial distribution of activated neurones, suggesting that the gene expression change resulted from specific receptor interaction. Repeated exposure to odorant or use of different concentrations did not change the pattern of c-fos induction. These results indicate that odorant-induced c-fos expression can be used to visualize odorant representations in the olfactory epithelium that reflect late cellular events regulated by adequate odorant receptor stimulation.

National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-16531 (URN)10.1111/j.1471-4159.2005.03159.x (DOI)15935076 (PubMedID)
Available from: 2007-10-05 Created: 2007-10-05 Last updated: 2012-02-18
3. Zonal ablation of the olfactory sensory neuroepithelium of the mouse: effects on odorant detection.
Open this publication in new window or tab >>Zonal ablation of the olfactory sensory neuroepithelium of the mouse: effects on odorant detection.
2004 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 20, no 7, 1858-1864 p.Article in journal (Refereed) Published
Abstract [en]

Olfactory sensory neurons that express a specific odorant receptor, out of a thousand different, are unevenly distributed within, but restricted to one of four zones of the neuroepithelial sheet in the nasal cavity in the mouse. This zonal restriction of neurons expressing the same odorant receptor may have consequences, e.g. in case of localized injury. We found that the chemical dichlobenil can produce specific and permanent ablation of neurons in odorant receptor expression zone 1, while a higher dichlobenil dose causes reversible toxicity in neighboring zones. In behavior tests, mice lacking part of the olfactory epithelium had an increased detection threshold concentration of two-four orders of magnitude for some odorants but not others, resembling the phenomenon of specific hyposmia. This indicates that the broad tuning properties of single odorant receptors and their large number cannot fully compensate for loss of the receptor(s) with the highest sensitivity for a particular odorant.

Keyword
Acetates, Animals, Benzene, Male, Mice, Mice; Inbred C57BL, Odors, Olfactory Mucosa/cytology, Olfactory Receptor Neurons/*physiology, Pyridazines, Smell/*physiology
Identifiers
urn:nbn:se:umu:diva-16662 (URN)10.1111/j.1460-9568.2004.03634.x (DOI)15380007 (PubMedID)
Available from: 2007-10-08 Created: 2007-10-08 Last updated: 2011-05-26
4. Regional differences in turnover of olfactory sensory neurons in the adult
Open this publication in new window or tab >>Regional differences in turnover of olfactory sensory neurons in the adult
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5324 (URN)
Available from: 2006-09-19 Created: 2006-09-19 Last updated: 2010-01-13Bibliographically approved

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