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The Bmi1 polycomb gene as a target for therapies against retinal degeneration
Author(s) -
ARSENIJEVIC Y,
VAN LOHUIZEN M,
ZENCAK D
Publication year - 2009
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2009.2236.x
Subject(s) - bmi1 , outer nuclear layer , retinal degeneration , biology , apoptosis , retinitis pigmentosa , microbiology and biotechnology , retina , stem cell , genetics , neuroscience
Purpose In several neurodegenerative diseases 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 widely used to study photoreceptor (PR) loss. Methods We used different knockout mouse models to reveal whether proteins involved in the cell cycle regulation are responsible for photoreceptor loss in the Rd1 mouse. Results At P12, an early stage of the disease, Rd1 mice displayed an increased expression of CDK4 and CDK2 among PR nuclei. PRs also undergo DNA synthesis. At P12, the polycomb protein Bmi1 was expressed in virtually all the nuclei in the inner and outer nuclear layer of both wild‐type (WT) and Rd1 mice. Bmi1 promotes cell cycle progression via the repression of tumor suppressor genes. We reasoned that Bmi1 deletion could impede the aberrant CDK reactivation that characterizes neuronal apoptosis and may therefore delay retinal degeneration. We compared the histology of WT, Rd1 and Rd1;Bmi1‐/‐ and observed the presence of 7 rows of PRs in Rd1;Bmi1‐/‐ mice at P33, while Rd1 littermates displayed a single scattered row of PRs. ERG recordings revealed the ability of Rd1:Bmi1‐/‐ retinas to respond to light stimuli. Both DNA synthesis and CDK4 were strongly decreased in Rd1;Bmi1‐/‐ mice, respectively by 70% and 50% as compared to Rd1 littermates. Conclusion In conclusion, our data show for the first time a mechanism of retina degeneration involving a reactivation of the cell cycle that precedes PR death in Rd1 mice and reveal that the partial inhibition of cell cycle re‐entry strongly delays PR loss.