Caspase-3 in postnatal retinal development and degeneration.
OBJECTIVE
The primary purpose of this study was to evaluate the impact of caspase-3 ablation on photoreceptor degeneration in the rd-1 mouse. Concurrently, the role of caspase-3 in postnatal retinal development was evaluated. Caspase-3 is an important effector caspase that mediates many of the terminal proteolytic events of apoptosis. Its activation has been demonstrated in rodent models of photoreceptor degeneration and its ablation results in exencephaly and neonatal death.


METHODS
Retinal morphometry was performed at the light microscopic level in caspase-3 mutant mice from PN0 through PN23, and in rd-1/caspase-3 double mutant mice at PN14, -16, and -18. This was supplemented by terminal dUTP transferase nick end labeling (TUNEL) and immunohistochemical staining for activated caspase-3, rhodopsin, factor VII-related antigen and proliferating cell nuclear antigen (PCNA).


RESULTS
Caspase-3-deficient animals display marginal microphthalmia, peripapillary retinal dysplasia, delayed regression of vitreal vasculature, and retarded apoptotic kinetics of the inner nuclear layer. Ablation of caspase-3 provided transient photoreceptor protection in rd-1, but TUNEL-positive rod death proceeded, despite the absence of caspase-3 activation.


CONCLUSIONS
In vivo, caspase-3 is not critical for rod photoreceptor development, nor does it play a significant role in mediating pathologic rod death. Peripapillary dysplastic lesions suggest that there is delayed fusion of the optic fissure, and inner nuclear layer abnormalities indicate a cell-specific dependency on the mitochondria-caspase axis during development. The temporal nature of apoptotic retardation in the absence of caspase-3 implies the presence of caspase-independent mechanisms of developmental and pathologic cell death.
Zeiss
Caroline J
CJ
Section of Comparative Medicine, Yale School of Medicine, New Haven, Connecticut 06520, USA. caroline.zeiss@yale.edu
Neal
Jason
J
Johnson
Elizabeth A
EA
D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D016923:Cell Death; D004789:Enzyme Activation; D005167:Factor VII / Q000378:metabolism; D005260:Female; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020419:Photoreceptor Cells, Vertebrate / Q000201:enzymology / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012160:Retina / Q000201:enzymology / Q000254:growth & development*; D012162:Retinal Degeneration / Q000201:enzymology* / Q000473:pathology; D012243:Rhodopsin / Q000378:metabolism
D000941:Antigens; D018809:Proliferating Cell Nuclear Antigen; C031500:factor VII related antigen; D005167:Factor VII; D012243:Rhodopsin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases