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Evidence for gradients of gene expression correlating with zonal topography of the olfactory sensory map
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Molecular Biology.
Umeå University, Faculty of Medicine, Molecular Biology.
Umeå University, Faculty of Medicine, Molecular Biology.
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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.

Place, publisher, year, edition, pages
2001. Vol. 18, no 3, 283-295 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-5321DOI: 10.1006/mcne.2001.1019PubMedID: 11591129OAI: oai:DiVA.org:umu-5321DiVA: diva2:144803
Available from: 2006-09-19 Created: 2006-09-19 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Effects of retinoic acid in the mouse olfactory sensory systems
Open this publication in new window or tab >>Effects of retinoic acid in the mouse olfactory sensory systems
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A common characteristic in neurodegenerative diseases of the brain is death of specific neuronal populations. The lack of neuron proliferation and axon extension in most parts of the central nervous system leads to chronic loss of neurons in the case of injury or disease. Therefore it is essential to identify signals involved in neurogenesis and neuronal survival. A favorable model in which to study these events is the olfactory sensory neurons in the main olfactory epithelium and their target in the glomeruli of the olfactory bulb.

In spite of constant regeneration, each olfactory sensory neuron maintain expression of one particular odorant receptor and the specificity of their axonal projections to the glomeruli. Most mammals also have an accessory olfactory system consisting of the sensory neurons in the vomeronasal epithelium and their target area the accessory olfactory bulb. Differential expression of receptors and other genes divides the olfactory and vomeronasal epithelium into zones, but the function and mechanisms underlying the establishment of these zones are still elusive.

We identified four genes with graded expression patterns that correlated with the zones of the olfactory epithelium. One of the identified genes encodes a retinoic acid synthesizing enzyme, RALDH-2. We showed that RALDH-2 was expressed in a gradient in cells of the lamina propria underneath the olfactory epithelium, suggesting a possible retinoic acid regulation of zonally expressed genes in the olfactory epithelium.

To investigate the role of retinoic acid in the olfactory systems, we generated a transgenic mouse strain that selectively expressed a dominant negative retinoic acid receptor in mature olfactory and vomeronasal neurons. We found that subsequent to the establishment of axonal projections, the neurons of both olfactory systems died prematurely by retrograde caspase-3 activation. In the main olfactory system the onset of apoptosis was associated with the appearance of incorrect heterogenous glomeruli with axons of more than one OR identity. Additionally, the activity regulated cell adhesion molecule kirrel-2 was down regulated suggesting an additional regulation of this gene by retinoic acid. Deficient retinoic acid signaling in olfactory sensory neurons could thus induce apoptosis by changing the parameters for axonal competition by neural activity and kirrel-2 expression.

We found evidence for a selective neuronal death in the accessory olfactory system of the dnRAR mice, where only vomeronasal sensory neurons belonging to the basal zone died by retrograde caspase-3 activation. This implies that the two populations of sensory neurons in the vomeronasal epithelium differently depend on retinoic acid for their survival.

Place, publisher, year, edition, pages
Umeå: Molekylärbiologi (Medicinska fakulteten), 2007. 63 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1124
Keyword
olfactory, retinoic acid, neuron survival
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-1371 (URN)978-91-7264-375-8 (ISBN)
Public defence
2007-10-12, Major Groove, 6L, NUS, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2007-09-26 Created: 2007-09-26 Last updated: 2009-05-25Bibliographically approved
2. Molecular and functional anatomy of the mouse olfactory epithelium
Open this publication in new window or tab >>Molecular and functional anatomy of the mouse olfactory epithelium
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
olfactory epithelium, odorant receptor, zone, odorant, gene expression, cell specification, c-Fos, dichlobenil, olfactometry, proliferation
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-868 (URN)91-7264-138-X (ISBN)
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
3. Zonal organization of the mouse olfactory systems
Open this publication in new window or tab >>Zonal organization of the mouse olfactory systems
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Animals survey their environment for relevant odorous chemical compounds by means of the olfactory system. This system is in most vertebrates divided into a main and accessory olfactory system with two specialized neuroepithelia, the olfactory and the vomeronasal epithelium, respectively. The sensory neurons reside in these epithelia and together the neurons have an extraordinary sensitivity and are capable of detecting a vast number of different chemical molecules. After processing the chemical information, behavior may be altered. The information about a chemicals structure is deconstructed into a format that the brain may process. This is facilitated by organizing sensory neurons into a map and that the individual neuron responds only to one chemical feature. The sensory maps appear to have zones with different neuronal subpopulations. This thesis is addressing the fact that establishment, maintenance and function of these zones are unknown.

We identify a gene (NQO1) to be selectively expressed in defined zone of the olfactory and the vomeronasal epithelia, respectively. NQO1-positive and negative axons segregate within the olfactory nerve and maintain a zonal organization when reaching olfactory bulb target neurons. These results indicate that one zone of both the accessory and the main olfactory projection maps is composed of sensory neurons specialized in reducing environmental and/or endogenously produced quinones via an NQO1-dependent mechanism.

In addition, we have identified genes expressed in a graded manner that correlates with the dorsomedial-ventrolateral zonal organization of the olfactory epithelia. Considering the known functions of identified genes in establishment of cell specificity and precise axonal targeting, we suggest that zonal division of the primary olfactory systems is maintained, during continuous neurogenesis, as a consequence of topographic counter gradients of positional information.

The vomeronasal sensory neurons (VSN) are organized into an apical and a basal zone. The zones differ in expression of e.g. chemosensory receptor families and Gα protein subunits (Gαi2 and Gαo). We have analyzed transgenic mice (OMP-dnRAR) in which the VSNs are unresponsive to the function of one of the genes identified herein (RALDH2). The phenotype observed suggests that endogenous produced retinoic acid is selectively required for postnatal survival of neurons in the Gαo-positive zone. Analyses of another mouse line target deleted in the Gαi2 gene (Gαi2 mutant) reveal a cellular phenotype that is opposite to that of OMP-dnRAR mice. Consequently in these mice, the apical Gαi2-positive zone is reduced whereas VSNs in the basal zone are not affected.

Several social and reproductive behaviors are under the influence of the vomeronasal organ. We have analyzed some behavioral consequences of having deficient neurons that corresponds to either of the two zones. We propose that cues important for aggressive behavior are detected by apical vomeronasal zone, while cues detected by both apical and basal VSNs influence gender preference behavior.

Place, publisher, year, edition, pages
Umeå: Molekylärbiologi, 2004. 116 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 911
Keyword
Molecular biology, olfactory, vomeronasal, gene expression, zone, organization, behavior, Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-336 (URN)91-7305-706-1 (ISBN)
Public defence
2004-10-01, Major Groove, 6L, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2004-11-22 Created: 2004-11-22 Last updated: 2010-01-29Bibliographically approved

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