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- Login, Hande,1985-Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Staffan Bohm (author)
Activity-regulated retinoic acid signaling in olfactory sensory neurons
- BookEnglish2014
Publisher, publication year, extent ...
- Umeå :Umeå Universitet,2014
- 55 s.
- electronicrdacarrier
Numbers
- LIBRIS-ID:oai:DiVA.org:umu-89022
- ISBN:9789176010648
- https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-89022URI
Supplementary language notes
- Language:English
- Summary in:English
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- SwePubSwePub
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Series
- Umeå University medical dissertations,0346-6612 ;1653
Notes
- 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.
Subject headings and genre
- MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
- MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
- mouse olfactory system
- RA
- neuronal activity
- CNG
- Cyp26B1
- BACE1
- Kirrel-2
- molekylärbiologi
- Molecular Biology
Added entries (persons, corporate bodies, meetings, titles ...)
- Bohm, StaffanUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)(Swepub:umu)stbo0001 (thesis advisor)
- Alenius, MattiasLinköping University (opponent)
- Umeå universitetInstitutionen för molekylärbiologi (Medicinska fakulteten) (creator_code:org_t)
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