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Proapoptotic Bcl-2 Family Members, Bax and Bak, Are Essential for Developmental Photoreceptor Apoptosis

¹From the F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Philadelphia, Pennsylvania; the ²Graduate Program in Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; the ⁶Departments of Medicine, ³Pathology and Laboratory Medicine, ⁴Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania; and the ⁵Department of Ophthalmology, Scheie Eye Institute, Philadelphia, Pennsylvania.

PURPOSE. Apoptosis has been implicated in retinal development and degeneration, but the specific apoptotic pathways used are incompletely understood. The purpose of this study was to characterize the roles in retinal development of the proapoptotic Bcl-2 family members Bax and Bak.

METHODS. Eyes from mice at postnatal day (P)7, during the peak of developmental apoptosis in the retina, were processed for TdT-dUTP terminal nick-end labeling (TUNEL) to determine whether Bax knockout or double Bax/Bak knockout causes a defect in developmental apoptosis. Adult (>2-month-old) eyes from wild-type, Bak^-/-, Bax^-/-, and Bax^-/-Bak^-/- mice were analyzed by histology and immunocytochemistry to identify persistent retinal cells.

RESULTS. Adult Bax^-/-Bak^-/- eyes showed significant increases in the number of inner retinal cells, with an almost complete absence of TUNEL-positive cell death at P7. Some of these persistent cells in the inner retina notably included rod photoreceptors that normally undergo apoptosis after failure to migrate to the outer retina. These inner nuclear layer (INL) rods contained markers of early rod differentiation: rod opsin, arrestin, and recoverin. However, they did not form ectopic outer segments or contain the associated markers ROM-1, peripherin-2, and RP1.

CONCLUSIONS. Bax and Bak are important for retinal development and are the first apoptotic factors identified as essential for developmental photoreceptor apoptosis. Future studies will investigate the potential role of Bax and Bak in mediating pathologic photoreceptor death.

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