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Forkhead box N4 (FoxN4) triggers context-dependent differentiation in the developing chick retina and neural tube
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.
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.
(English)In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436Article in journal (Refereed) Submitted
Keyword [en]
Chicken, retinal development, Lim1, Prox1, retinal progenitor cells, Sox2
National Category
Neurosciences
Research subject
Developmental Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-180007OAI: oai:DiVA.org:uu-180007DiVA: diva2:547560
Available from: 2012-08-28 Created: 2012-08-28 Last updated: 2017-12-07Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 821
Keyword
Regeneration, Proliferation, Neurotransmitters, Müller cells, Differentiation, Retinal repair, Neurogenesis
National Category
Neurosciences Other Basic Medicine
Research subject
Medical Science
Identifiers
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)
Opponent
Supervisors
Note

Doctor of Philosophy (Faculty of Medicine)

Available from: 2012-11-22 Created: 2012-08-28 Last updated: 2013-02-11Bibliographically approved
2. The Heterogenic Final Cell Cycle of Retinal Horizontal Cells
Open this publication in new window or tab >>The Heterogenic Final Cell Cycle of Retinal Horizontal Cells
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The cell cycle is a highly complex process that is under the control of several pathways.  Failure to regulate and/or complete the cell cycle often leads to cell cycle arrest, which may be followed by programmed cell death (apoptosis). One cell type that has a variety of unique cell cycle properties is the horizontal cell of the chicken retina. In this thesis we aimed to characterize the final cell cycle of retinal horizontal cells. In addition, the regulation of the cell cycle and the resistance to apoptosis of retinal horizontal cells are investigated.

Our results show that the final cell cycle of Lim1-expressing horizontal progenitor cells is heterogenic and three different cell cycle behaviors can be distinguished. The horizontal cells are generated by: (i) an interkinetic nuclear migration with an apical mitosis; (ii) a final cell cycle with an S-phase that is not followed by mitosis, such cells remain with a fully or partially replicated genome; or (iii) non-apical (basal) mitoses. Furthermore, we show that the DNA damage response pathway is not triggered during the heterogenic final cell cycle of horizontal progenitor cells. However, chemically induced DNA damage activated the DNA damage response pathway without leading to cell cycle arrest, and the horizontal progenitor cells entered mitosis in the presence of DNA damage. This was not followed by apoptosis, despite the horizontal cells being able to functionally activate p53, p21CIP1/waf1, and caspase-3. Finally, we show that FoxN4 is expressed in horizontal progenitor cells and is required for their generation. Over-expression of FoxN4 causes cell death in several neuronal retinal cell types, except horizontal cells, where it results in an overproduction.

In conclusion, in this thesis, a novel cell cycle behavior, which includes endoreplication not caused by DNA damage and a basal mitosis that can proceed in the presence of DNA damage, is described. The cell cycle and cell survival processes are of particular interest since retinal horizontal cells are suggested to be the cell-of-origin for retinoblastoma. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 995
Keyword
Apoptosis, Checkpoint, DNA damage, Differentiation, Heteroploid, Endoreplication, Proliferation, Tumor
National Category
Natural Sciences Medical and Health Sciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-222559 (URN)978-91-554-8941-0 (ISBN)
Public defence
2014-06-04, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-05-14 Created: 2014-04-11 Last updated: 2014-06-30Bibliographically approved

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Ring, Henrik

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