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Retinoic acid receptor and CNGA2 channel signaling are part of a regulatory feedback loop controlling axonal convergence and survival of olfactory sensory neurons
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). (Bohm)
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Berghard)
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). (Bohm)
2012 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 2, 617-627 p.Article in journal (Refereed) Published
Abstract [en]

Little is known about the identities and functions of extracellular signaling molecules that work in concert with neuronal activity to regulate refinement and maintenance of the mouse olfactory sensory map. We show that expression of a dominant negative retinoic acid receptor (RAR) in olfactory sensory neurons (OSNs) increased the number of glomeruli that incorrectly contained OSN axons expressing different odorant receptors. This phenotype became apparent postnatally, coincided with increased cell death, and was preceded by increased Neuropilin-1 and reduced Kirrel-2 expressions. Kirrel-2-mediated cell adhesion influences odorant receptor-specific axonal convergence and is regulated by odorant receptor signaling via the olfactory cyclic nucleotide-gated (CNG) ion channel. Accordingly, we found that inhibited RAR function correlated with reduced CNG channel expression. Naris occlusion experiments and analysis of CNG channel-deficient mice further indicated that RAR-regulated CNG channel levels influenced the intrinsic neuronal activity required for cell survival in the absence of odor stimulation. Finally, we showed that CNG channel activity regulated expression of the retinoic acid-degrading enzyme Cyp26B1. Combined, these results identify a novel homeostatic feedback mechanism involving retinoic acid metabolism and CNG channel activity, which influences glomerular homogeneity and maintenance of precisely connected OSNs.

Place, publisher, year, edition, pages
Federation of American Society of Experimental Biology (FASEB) , 2012. Vol. 26, no 2, 617-627 p.
Keyword [en]
retinoids, neuronal activity, caspase-3, Kirrel-2, Neuropilin-1
National Category
Cell and Molecular Biology
Research subject
URN: urn:nbn:se:umu:diva-55746DOI: 10.1096/fj.11-192450ISI: 000300485700015PubMedID: 22009938OAI: diva2:529178
Available from: 2012-05-29 Created: 2012-05-29 Last updated: 2014-05-22Bibliographically approved
In thesis
1. Activity-regulated retinoic acid signaling in olfactory sensory neurons
Open this publication in new window or tab >>Activity-regulated retinoic acid signaling in olfactory sensory neurons
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of the studies included in the thesis is to better understand the interplay between neuronal activity-dependent gene regulation and the bioactive vitamin A metabolite all-trans-retinoic acid (RA) during postnatal development, refinement and maintenance of precise neuronal connectivity using the olfactory sensory neuron (OSN) in the olfactory epithelium (OE) of genetically modified mice as a model. We show that:

Inhibition of RA receptor (RAR)-mediated transcription in OSNs reduces expression of the olfactory cyclic nucleotide-gated (CNG) ion channel, which is required for odorant receptor (OR)-mediated stimulus transduction. This, results in increased OSN death and errors in precise connectivity. The increased cell death may be a consequence of reduced intrinsic excitability and/or reduced influx of Ca2+ ions while the errors in connectivity may be due to altered OR-dependent expression of axonal guidance proteins, such as Kirrel-2 and Neuropilin-1.

Expression of the RA catabolic enzyme Cyp26B1 in OSNs is positively regulated by RAR-mediated transcription as well as sensory stimulation in a CNG channel-dependent manner. This shows that neuronal activity and local vitamin A metabolism are parts of novel regulatory feedback loop controlling precise connectivity and neuronal survival. The feedback loop may be a form of homeostatic plasticity in response to global changes in neuronal activity.

BACE1, an enzyme is implicated in Alzheimer´s disease, and Cyp26B1 are inversely regulated by CNG channel-dependent sensory stimulation. Cyp26B1 expression is switched on at birth, forms a topographic expression gradient in OE and inhibits BACE1 expression into an inverse counter gradient. Taken together these results reveal a novel neuronal activity-dependent mechanism by which sensory stimuli can shape spatial gene expression via altered RA bioavailability.

Increased Cyp26B1 expression stimulates turnover of OSNs during adult neurogenesis by a non-cell-autonomous mechanism. The gradient of Cyp26B1 expression correlates with spatially-regulated diversification of OSNs into subpopulations that express different subsets of OR genes. Cyp26B1 expression influences spatial OR diversification of OSNs by two different mechanisms. In the ventrolateral OE, Cyp26B1 inhibits OR expression by blocking OSN differentiation at a stage that may be associated with the cell intrinsic mechanism regulating OR gene choice. In the dorsomedial OE the expression frequency of some ORs is unaltered while other increases, presumably as a consequence of neuronal activity-dependent competition. A probable function of graded and activity-dependent Cyp26B1 expression is to form a topographic partitioning of the olfactory sensory map into functional domains, which gradually differ from each other with regard to experience-driven plasticity and neurogenic potential along the dorsomedial-ventrolateral axis of OE.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2014. 55 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1653
mouse olfactory system, RA, neuronal activity, CNG, Cyp26B1, BACE1, Kirrel-2
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
urn:nbn:se:umu:diva-89022 (URN)978-91-7601-064-8 (ISBN)
Public defence
2014-06-12, Major Groove, Department of Molecular Biology, By 6L, Umeå University, Umeå, 10:00 (English)
Available from: 2014-05-22 Created: 2014-05-20 Last updated: 2015-08-10Bibliographically approved

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Öztokatli, HandeHörnberg, MariaBerghard, AnnaBohm, Staffan
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