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Effects of retinoic acid in the mouse olfactory sensory systems
Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
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 [en]
olfactory, retinoic acid, neuron survival
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-1371ISBN: 978-91-7264-375-8 (print)OAI: oai:DiVA.org:umu-1371DiVA: diva2:140788
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
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
Show others...
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: 2017-12-14Bibliographically approved
2. Retinoic acid receptor-dependent survival of olfactory sensory neurons in postnatal and adult mice.
Open this publication in new window or tab >>Retinoic acid receptor-dependent survival of olfactory sensory neurons in postnatal and adult mice.
2006 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 12, 3281-3291 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-16510 (URN)10.1523/JNEUROSCI.4955-05.2006 (DOI)16554478 (PubMedID)
Available from: 2007-10-04 Created: 2007-10-04 Last updated: 2017-12-14
3. Apical and basal vomeronasal neurons differentially depend on retinoic acid receptor function for survival during postnatal development of segregated axonal projections.
Open this publication in new window or tab >>Apical and basal vomeronasal neurons differentially depend on retinoic acid receptor function for survival during postnatal development of segregated axonal projections.
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2585 (URN)
Available from: 2007-09-26 Created: 2007-09-26 Last updated: 2010-01-13Bibliographically approved
4. Retinoic acid receptor-dependent gene expression promotes olfactory sensory neuron survival by maintaining precise neronal connections
Open this publication in new window or tab >>Retinoic acid receptor-dependent gene expression promotes olfactory sensory neuron survival by maintaining precise neronal connections
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2586 (URN)
Available from: 2007-09-26 Created: 2007-09-26 Last updated: 2010-01-13Bibliographically approved

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