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Tissue-Specific Stem Cells
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Bmi1 Distinguishes Immature Retinal Progenitor/Stem Cells from the Main Progenitor Cell Population and Is Required for Normal Retinal Development†‡§
Article first published online: 14 JUN 2010
DOI: 10.1002/stem.462
Copyright © 2010 AlphaMed Press
Additional Information
How to Cite
Chatoo, W., Abdouh, M., Duparc, R.-H. and Bernier, G. (2010), Bmi1 Distinguishes Immature Retinal Progenitor/Stem Cells from the Main Progenitor Cell Population and Is Required for Normal Retinal Development. STEM CELLS, 28: 1412–1423. doi: 10.1002/stem.462
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Author contributions: W.C.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing; M.A.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing; R.-H.D.: collection and assembly of data; G.B.: conception and design, financial support, administrative support, data analysis and interpretation, manuscript writing, final approval of manuscript. W.C. and M.A. contributed equally to this article.
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Disclosure of potential conflicts of interest is found at the end of this article.
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First published online in STEM CELLS EXPRESS June 14, 2010.
Publication History
- Issue published online: 18 AUG 2010
- Article first published online: 14 JUN 2010
- Manuscript Accepted: 31 MAY 2010
- Manuscript Received: 6 NOV 2009
Funded by
- Natural Science and Engineering Research Council of Canada
- Canadian Institutes of Health Research
- Foundation Fighting Blindness Canada
- Turmel Family Foundation for Macular Degeneration Research
- Fonds de Recherche en Santé du Québec
- Fonds de Recherche en Ophtalmologie de l'Université de Montréal
Keywords:
- Bmi1;
- Stem cells;
- Progenitors;
- Retina;
- Self-renewal;
- Development
Abstract
The developing mammalian retina is generated by the proliferation and differentiation of multipotent retinal progenitor cells (RPCs) giving rise to neuronal and glial lineages. Whether an immature progenitor/stem cell subpopulation is present in the developing mammalian retina remains undefined. Deficiency in the polycomb group gene Bmi1 results in reduced proliferation and postnatal depletion of neural and hematopoietic stem cells. Here, we show that Bmi1 is required for the self-renewal of most immature RPCs and for postnatal retinal development. In the embryo, Bmi1 is highly enriched in a rare stage-specific embryonic antigen-1-positive RPC subpopulation expressing the stem cell markers Sox2, Lhx2, and Musashi. Gain-of-function experiments revealed that Bmi1 overexpression could convert RPCs having limited proliferation capacity into RPCs showing extensive proliferation and multiple differentiation capacities over time. At all developmental stages analyzed using the neurosphere assay, Bmi1 deficiency resulted in reduced proliferation and self-renewal of most immature RPCs. Reduced RPCs proliferation was also observed in the peripheral retina of Bmi1−/− fetus and newborn mice. The biological impact of these developmental anomalies was revealed by the reduced retinal diameter of Bmi1-deficient pups. P19Arf and p16Ink4a were upregulated in vivo and in vitro and coinactivation of p53, which lies downstream of p19Arf, partially restored Bmi1-deficient RPCs self-renewal phenotype. Bmi1 thus distinguishes immature RPCs from the main RPC population and is required for normal retinal development. STEM CELLS 2010;28:1412–1423