SUPPRESSION OF DEVELOPMENTAL RETINAL CELL-DEATH BUT NOT OF PHOTORECEPTOR DEGENERATION IN BAX-DEFICIENT MICE

PURPOSE. Bar, a member of the Bcl2 family of cell death regulators, in duces cell death by promoting the induction of apoptosis. Bax-deficien t mice were examined in this study to determine whether Bax is require d for cell death in the developing retina and for pathologic apoptotic photoreceptor degeneration resulting from the rd mutation. METHODS. R etinas from Bax-deficient mice and their wild-type siblings were harve sted at postnatal day (P) 7 and processed for TdT-dUTP terminal nick-e nd labeling (TUNEL) staining, and the number of nuclei containing frag mented DNA were counted. Adult retinas and optic nerves were processed for plastic-embedded 1-mu m sections, and the cross-sectional area wa s determined. The mutant Bax allele was outbred onto the C3H mouse str ain, which carries the rd allele. Retinas from these animals were exam ined histologically at P21 after most of the photoreceptor cell death had occurred. RESULTS. At P7, around the time of peak cell death in th e inner nuclear layer (INL), significantly fewer neurons in INL and ga nglion cell layer (GCL) were TUNEL positive in Bax-deficient mice than in their wild-type siblings. In adult Bax-deficient mice, the cross-s ectional area of the optic nerve was approximately 50% larger than in wild-type siblings, and the total number of retinal ganglion cell axon s was increased to 226%. The INL of Bax-deficient mice was thicker tha n normal. The Bax genotype did not affect the thickness or histologic appearance of the outer nuclear layer in retinas of mice with wild-typ e or mutant rd alleles. CONCLUSIONS. In the absence of the expression of the Bar gene, there is a profound increase in the survival of retin al ganglion cells that lasts into adulthood. Similarly, death of INL c ells is diminished but not completely abolished. The absence of Bax do es not, however, protect photoreceptors from naturally occurring cell death or degeneration induced by the rd mutation. This shows that Bax is involved to a variable degree in the control of developmental cell death in the retina and that not all apoptotic retinal cell deaths are controlled by Bax.