Transgenic Bcl-2 expressed in photoreceptor cells confers both death-sparing and death-inducing effects.
To examine its potential role within the retina as a modulator of cell death and photoreceptor degeneration, bcl-2 expression was targeted to the photoreceptors of transgenic mice by the human IRBP promoter. Three transgenic families were established, with levels of transgene expression between 0.2 and two-fold relative to that of endogenous bcl-2. The effect of bcl-2 expression on genetically programmed photoreceptor degeneration was evaluated by crossing these transgenic mice with mice that develop a rapid degeneration of rod photoreceptors due to expression of a distinct transgene, SV40 T antigen (Tag). Transgenic Bcl-2 was localized to photoreceptor inner segments and was capable of abrogating the activation of caspase activity and the resulting cell death associated with ectopic expression of Tag. However, Bcl-2 itself ultimately caused photoreceptor cell death and retinal degeneration. Several proteins not expressed normally in Tag or other transgenic retinas undergoing photoreceptor degeneration were induced in the Bcl-2 transgenic retinas. Analysis by mass spectroscopy identified one of these proteins as alphaA-crystallin, a member of a protein family that associates with cellular stress. Since Bcl-2 can promote as well as spare cell death in the same photoreceptor population, its potential utility in ameliorating photoreceptor death in human hereditary blinding disorders is compromised.
Quiambao
A B
AB
Department of Ophthalmology and Visual Sciences, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Tan
E
E
Chang
S
S
Komori
N
N
Naash
M I
MI
Peachey
N S
NS
Matsumoto
H
H
Ucker
D S
DS
Al-Ubaidi
M R
MR
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015152:Blotting, Northern; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004596:Electroretinography; D005136:Eye Proteins; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012177:Retinol-Binding Proteins / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000099214:Retinol-Binding Proteins, Interstitial
D020169:Caspases; D005136:Eye Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial