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Increased A-to-I RNA editing of the transcript for GABAA receptor subunit α3 during chick retinal development
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
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2010 (English)In: Visual Neuroscience, ISSN 0952-5238, E-ISSN 1469-8714, Vol. 27, no 5-6, 149-157 p.Article in journal (Refereed) Published
Abstract [en]

Adenosine-to-inosine (A-to-I) RNA editing is a cotranscriptional or posttranscriptional gene regulatory mechanism that increases the diversity of the proteome in the nervous system. Recently, the transcript for GABA type A receptor subunit α3 was found to be subjected to RNA editing. The aim of this study was to determine if editing of the chicken α3 subunit transcript occurs in the retina and if the editing is temporally regulated during development. We also raised the question if editing of the α3 transcript was temporally associated with the suggested developmental shift from excitation to inhibition in the GABA system. The editing frequency was studied by using Sanger and Pyrosequencing, and to monitor the temporal aspects, we studied the messenger RNA expression of the GABAA receptor subunits and chloride pumps, known to be involved in the switch. The results showed that the chick α3 subunit was subjected to RNA editing, and its expression was restricted to cells in the inner nuclear and ganglion cell layer in the retina. The extent of editing increased during development (after embryonic days 8–9) concomitantly with an increase of expression of the chloride pump KCC2. Expression of several GABAA receptor subunits known to mediate synaptic GABA actions was upregulated at this time. We conclude that editing of the chick GABAA subunit α3 transcript in chick retina gives rise to an amino acid change that may be of importance in the switch from excitatory to inhibitory receptors.

Place, publisher, year, edition, pages
2010. Vol. 27, no 5-6, 149-157 p.
Keyword [en]
Chloride ion channel, GABA(A) subunits, GABA receptor, KCC2, mRNA expression, Posttranscriptional modification
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-143655DOI: 10.1017/S0952523810000180ISI: 000285477900002PubMedID: 20843408OAI: oai:DiVA.org:uu-143655DiVA: diva2:391040
Available from: 2011-01-24 Created: 2011-01-24 Last updated: 2013-12-18Bibliographically approved
In thesis
1. Characterization of Retinal Progenitor Cells: Focus on Proliferation and the GABAA Receptor System
Open this publication in new window or tab >>Characterization of Retinal Progenitor Cells: Focus on Proliferation and the GABAA Receptor System
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

One strategy to repair an injured or degenerated retina is to stimulate the replacement of damaged or dead neurons with cells derived from endogenous stem- or progenitor cells. A successful strategy requires knowledge about how the proliferation and differentiation of the endogenous cells are regulated. In particular, this knowledge will be important in the establishment of protocols that produce sufficient numbers of specific neurons. The main aim of this thesis was to find and characterise factors regulating the proliferation and differentiation of retinal progenitor cells (RPCs) and hence, contribute to the knowledge of how to use progenitor cells for retinal repair.   

The major result in this thesis is that GABA contributes to and maintains RPC proliferation. Inhibition of GABAA receptors decreases the proliferation of non-pigmented ciliary epithelial (NPE) cells and RPCs in the intact retina. We propose that this effect is mediated through changes in the membrane potential and voltage-gated calcium channels, which in turn regulate components of the cell cycle. Furthermore, we show that one of the endogenous RPC sources, the Müller cells, consists of two subpopulations based on Pax2 expression. This is interesting because Pax2 may suppress the neurogenic potential, characterised by de-differentiation and proliferation, in Müller cells. Finally, we show that over-expression of FoxN4 induces differentiation-associated transcription factors in the developing chick retina. However, FoxN4 over-expression did not trigger differentiation of NPE cells. These results indicate that the intrinsic properties of the RPCs are determinant for FoxN4-induced differentiation.

The results presented in this thesis advance our understanding of how specific cells may be generated from different sources of RPCs. Our results show that the different sources are highly diverse in their potential to proliferate and produce neurons. GABA, Pax2 and FoxN4 may be factors to consider when designing strategies for retinal repair. However, the results indicate that the specific responses to these factors are highly associated with the specific properties of the progenitor cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 60 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 821
Regeneration, Proliferation, Neurotransmitters, Müller cells, Differentiation, Retinal repair, Neurogenesis
National Category
Neurosciences Other Basic Medicine
Research subject
Medical Science
urn:nbn:se:uu:diva-180011 (URN)978-91-554-8489-7 (ISBN)
Public defence
2012-12-13, B41, BMC, Husargatan 3, Uppsala, 10:00 (English)

Doctor of Philosophy (Faculty of Medicine)

Available from: 2012-11-22 Created: 2012-08-28 Last updated: 2013-02-11Bibliographically approved

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