NON-CELL-AUTONOMOUS PHOTORECEPTOR DEGENERATION IN RDS MUTANT MICE MOSAIC FOR EXPRESSION OF A RESCUE TRANSGENE

The inherited retinal dystrophies represent a large and heterogenous g roup of hereditary neurodegenerations, for many of which, the molecula r defect has been defined. However, the mechanism of cell death has no t been determined for any form of retinal degeneration. The retinal de generation slow (rds-/-) mutation of mice is associated with nondevelo pment of photoreceptor outer segments and gradual death of photorecept or cell bodies, attributed to the absence of the outer segment protein rds/peripherin. Here, we examined the effects of a transgene encoding normal rds/peripherin that had integrated into the X-chromosome in ma le and female rds-/-mutant retinas. In 2-month-oId transgenic males an d homozygous-transgenic females on rds-/-, we observed virtually compl ete rescue of both the outer segment nondevelopment and photoreceptor degeneration. In contrast, hemizygous-transgenic rds-/- female litterm ates showed patchy distributions of the transgene mRNA, by in situ hyb ridization analysis, and of photoreceptor cells that contain outer seg ments. This pattern is consistent with random inactivation of the X-ch romosome and mosaic expression of the transgene. Surprisingly, we obse rved significant photoreceptor cell loss in both transgene-expressing and nonexpressing patches in hemizygous female retinas. These observat ions were supported by nuclease protection analysis, which showed nota bly lower than predicted levels of transgene mRNA in retinas from hemi zygous females compared with male and homozygous female littermates. T his phenotype suggests an important component of non-cell-autonomous p hotoreceptor death in rds-/- mutant mice. These results have significa nce to both the etiology and potential treatment of human inherited re tinal degenerations.