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Horizontal cell progenitors arrest in G2-phase and undergo terminal mitosis on the vitreal side of the chick retina
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.
2009 (English)In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 330, no 1, 105-113 p.Article in journal (Refereed) Published
Abstract [en]

We have addressed the question when horizontal cells in the chick retina are generated and undergo their terminal mitosis. Horizontal cell progenitors replicate their DNA early and migrate bi-directionally to the horizontal cell layer. It was hypothesized that the cells undergo mitosis directly after replication and migrate as post-mitotic transition cells before differentiating to horizontal cells. However, our results show that cells expressing markers for the axon-bearing and the axon-less subtypes of horizontal cells undergo terminal mitosis while residing on the vitreal side of the retina. By combining horizontal cell transcription factors Lim1, Isl1 and Prox1 labeling with phospho-histone H3, a marker for mitosis, we demonstrate that all or a clear majority of vitreal mitoses are undertaken by the horizontal cell committed progenitors. The pattern of cells that incorporated the thymidine analogue EdU implied that the progenitors replicated their genome while migrating towards the vitreal side. Upon arrival to the vitreal retina they become arrested for about two days prior to mitosis. Hence, cells expressing horizontal cell markers are arrested in G2-phase on the vitreal side of the retina. These results support the existence of committed progenitors that give rise to horizontal cells and that those cells become arrested in G2-phase before undergoing terminal mitosis on the vitreal side of the retina followed by migration to the horizontal cell layer. The results also indicate that the regulation of the transition from G2-phase to mitosis is important for the development of these committed progenitor cells.

Place, publisher, year, edition, pages
Elsevier , 2009. Vol. 330, no 1, 105-113 p.
Keyword [en]
Cell cycle, Differentiation, Development, EdU, Prox1, Lim1, Stem cell
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-120381DOI: 10.1016/j.ydbio.2009.03.013ISI: 000266300800010PubMedID: 19324032OAI: oai:DiVA.org:uu-120381DiVA: diva2:303238
Available from: 2010-03-11 Created: 2010-03-11 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Generation of Retinal Neurons: Focus on the Proliferation and Differentiation of the Horizontal Cells and their Subtypes
Open this publication in new window or tab >>Generation of Retinal Neurons: Focus on the Proliferation and Differentiation of the Horizontal Cells and their Subtypes
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

We have used the chicken retina as a model for investigating cell cycle regulation and cell fate commitment during central nervous system development. This thesis focuses on the characterization of and commitment to the horizontal cell fate in the retina. Horizontal cells are interneurons that provide intraretinal signal processing prior to information relay to the brain. We have identified molecular markers that selectively distinguish the three subtypes of horizontal cells, previously described in the chicken retina based on morphology. Subtype specific birth-dating revealed that horizontal cell subtypes are generated consecutively by biased progenitors that are sensitive to the inhibitory effects of follistatin. Follistatin stimulates proliferation in progenitors by repressing the differentiation signal of activin. Initially, injection of follistatin led to a decrease in committed horizontal cells but as the inhibitory effect dissipated it resulted in an increased number of horizontal cells. During development committed horizontal cell progenitors migrate to the vitreal side of the retina where they become arrested in G2-phase for approximately two days. When the arrest is overcome the horizontal cell progenitors undergo ectopic mitosis followed by migration to their designated layer. The G2-phase arrest is not triggered or maintained by any of the classic G2-arrest pathways such as DNA damage or stress. Nevertheless, we show that the cyclin B1-Cdk1 complex has a central role in maintaining this G2-phase arrest. Two transcription factors, FoxN4 and Ptf1a, are required for the generation of horizontal cells. We show that these factors are also sufficient to promote horizontal cell fate. Overexpression of FoxN4 and Ptf1a resulted in an overproduction of horizontal- and amacrine cells at the expense of ganglion- and photoreceptor cells. We identified Atoh7, a transcription factor required for the generation of ganglion cells, as a Ptf1a transcriptional target for downregulation. Our data support a common horizontal/amacrine lineage separated from the ganglion/photoreceptor lineage by the action of Ptf1a. In conclusion, these data describe several novel characteristics of horizontal cells enhancing our understanding of neural development and cell fate commitment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitalis Upsaliensis, 2011. 48 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 672
Keyword
FoxN4, Ptf1a, PH3, G2-phase, Cell cycle arrest, Differentiation, Fate, Commitment, Neurogenesis, Follistatin
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-150886 (URN)978-91-554-8074-5 (ISBN)
Public defence
2011-05-28, B42, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2011-05-06 Created: 2011-04-07 Last updated: 2011-07-01Bibliographically approved

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Boije, HenrikEdqvist, Per-Henrik D.Hallböök, Finn

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