Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins.
The epigenetic regulator Bmi1 controls proliferation in many organs. Reexpression of cell cycle proteins such as cyclin-dependent kinases (CDKs) is a hallmark of neuronal apoptosis in neurodegenerative diseases. Here we address the potential role of Bmi1 as a key regulator of cell cycle proteins during neuronal apoptosis. We show that several cell cycle proteins are expressed in different models of retinal degeneration and required in the Rd1 photoreceptor death process. Deleting E2f1, a downstream target of CDKs, provided temporary protection in Rd1 mice. Most importantly, genetic ablation of Bmi1 provided extensive photoreceptor survival and improvement of retinal function in Rd1 mice, mediated by a decrease in cell cycle markers and regulators independent of p16(Ink4a) and p19(Arf). These data reveal that Bmi1 controls the cell cycle-related death process, highlighting this pathway as a promising therapeutic target for neuroprotection in retinal dystrophies.
Unit of Gene Therapy and Stem Cell Biology, Jules-Gonin Eye Hospital,  University of Lausanne, 1004 Lausanne,  Switzerland.
Dusan
D
Zencak
Karine
K
Schouwey
Danian
D
Chen
Per
P
Ekström
Ellen
E
Tanger
Rod
R
Bremner
Maarten
M
van Lohuizen
Yvan
Y
Arsenijevic
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006652:Histological Techniques; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012162:Retinal Degeneration / Q000378:metabolism*
C489421:Bmi1 protein, mouse; D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D011518:Proto-Oncogene Proteins; D063150:Polycomb Repressive Complex 1