May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Interference With Cell Cycle via Bmi1 Deletion Delays Photoreceptor Death in Rd1 Mice
Author Affiliations & Notes
  • D. Zencak
    Unit of Gene Therapy & Stem Cell Biology, Jules Gonin Eye Hospital, Lausanne, Switzerland
  • S. V. Crippa
    Unit of Gene Therapy & Stem Cell Biology, Jules Gonin Eye Hospital, Lausanne, Switzerland
  • E. Tanger
    Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands
  • M. Tekaya
    Unit of Gene Therapy & Stem Cell Biology, Jules Gonin Eye Hospital, Lausanne, Switzerland
  • D. Wanner
    Unit of Gene Therapy & Stem Cell Biology, Jules Gonin Eye Hospital, Lausanne, Switzerland
  • M. van Lohuizen
    Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands
  • Y. Arsenijevic
    Unit of Gene Therapy & Stem Cell Biology, Jules Gonin Eye Hospital, Lausanne, Switzerland
  • Y. Arsenijevic
    Unit of Gene Therapy & Stem Cell Biology, Jules Gonin Eye Hospital, Lausanne, Switzerland
  • Footnotes
    Commercial Relationships  D. Zencak, None; S.V. Crippa, None; E. Tanger, None; M. Tekaya, None; D. Wanner, None; M. van Lohuizen, None; Y. Arsenijevic, None; Y. Arsenijevic, None.
  • Footnotes
    Support  Swiss National Foundation, Pro Visu Foundation
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 3001. doi:
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      D. Zencak, S. V. Crippa, E. Tanger, M. Tekaya, D. Wanner, M. van Lohuizen, Y. Arsenijevic, Y. Arsenijevic; Interference With Cell Cycle via Bmi1 Deletion Delays Photoreceptor Death in Rd1 Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3001.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : In several neurodegenerative diseases (NDD), the reactivation of cell cycle proteins is a key event that precedes neuronal apoptosis. We asked whether a similar phenomenon occurs in Rd1 mice, a model of retinitis pigmentosa, thus we aimed to interfere with the cell cycle by knocking out Bmi1, a key promoter of cell cycle progression, in order to prevent photoreceptor (PR) death in Rd1 mice.

Methods: : We compared the histology of WT, Rd1 and Rd1;Bmi1-/- and Rd1;Bmi1;Ink4a/arf triple knockout (TKO) mice focusing our attention on cell cycle proteins and PR markers, and attested retinal function by ERG recordings.

Results: : Compared to WT littermates, Rd1 mice displayed an increased expression of E2F1, CDK4, andCDK2 among the nuclei of the ONL. PRs also incorporated BrdU, but were not positive for phosphoH3, thus showing a failure to complete the cell cycle, consistently with what was observed in other NDDs. The nuclear expression of Bmi1 in the ONL and INL of both P12 WT and Rd1 mice, led us to analyze Rd1;Bmi1-/- retinas, with the idea that Bmi1 deletion could impede aberrant cell cycle reactivation, and therefore delay retinal degeneration. Indeed, in Rd1;Bmi1-/- mice, PR loss was importantly delayed, with 6-8 rows of nuclei in the ONL at P30 compared to the single scattered row present in Rd1 littermates, and rescued PRs were functional as assessed by ERG. BrdU incorporation was strongly reduced in the ONL of Rd1;Bmi1-/- mice, showing that Bmi1 may interfere with cell cycle re-entry. Analysis of Rd1;Bmi1;Ink4a/arf TKO retinas revealed that Bmi1 deletion rescued the Rd1 phenotype independently of p16ink4a and p19arf.

Conclusions: : Our data show for the first time a mechanism of retinal degeneration involving a reactivation of the cell cycle that precedes PR death in Rd1 mice. The disease is strongly delayed in Rd1;Bmi1-/- mice, likely due to an interference with cell cycle progression, and occurs independently of the classical Bmi1 targets p16ink4a and p19arf. A detailed analysis of cell cycle markers in Rd1;Bmi1-/- is currently being completed.

Keywords: retinal degenerations: cell biology • neuroprotection • cell survival 
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