The role of cellular interactions in the mechanism of secondary cone photoreceptor degeneration in inherited retinal degenerations in which the mutation specifically affects rod photoreceptors was studied. We developed an organ culture model of whole retinas from 5-week-old mice carrying the retinal degeneration mutation, which at this age contain few remaining rods and numerous surviving cones cocultured with primary cultures of mixed cells from postnatal day 8 normal-sighted mice (C57BL͞6) retinas or retinal explants from normal (C57BL͞6) or dystrophic (C3H͞He) 5-week-old mice. After 7 days, the numbers of residual cone photoreceptors were quantified after specific peanut lectin or anti-arrestin antibody labeling by using an unbiased stereological approach. Examination of organ cultured retinas revealed significantly greater numbers of surviving cones (15-20%) if cultured in the presence of retinas containing normal rods as compared with controls or cocultures with rod-deprived retinas. These data indicate the existence of a diffusible trophic factor released from retinas containing rod cells and acting on retinas in which only cones are present. Because cones are responsible for high acuity and color vision, such data could have important implications not only for eventual therapeutic approaches to human retinal degenerations but also to define interactions between retinal photoreceptor types.Despite recent advances, our understanding of the mechanisms underlying visual malfunction and cell loss in retinitis pigmentosa (RP) has provided few clinically significant clues to improve retinal cell survival (1-3). RP forms a group of inherited photoreceptor dystrophies characterized largely by early features of rod photoreceptor impairment (1, 4). Most identified forms of RP are caused by defects in proteins restricted to rod photoreceptors (5-8). Yet, at various stages of the disease, a loss of the photopic function reflecting degeneration of cone photoreceptors is found consistently (1, 4). Of extreme importance for the patient, cone cell death and its functional consequences appear to be secondary events. No current data exist to account for cone cell death, but observations made on animal models of RP provide arguments for cone survival depending on the presence of rods. In several models with selective elimination of rods, secondary loss of cones is observed (9-11). The cause of rod cell death in these animals, either transgenic or spontaneous mutants, cannot account for direct cone cell loss (9-17). Putative mechanisms of cone cell death include the liberation of endotoxins by degenerating rods, environmental alteration, or deprivation of rod-derived trophic factor(s). Recent studies using chimeras of normal and transgenic mice carrying mutations in rods showed that photoreceptor cell death was diffuse rather than restricted to areas with mutations in rods, providing evidence for a role of cellular interactions between photoreceptors in survival and degeneration of these cells (18). Based on these dat...

Retinal transplants offer a potentially interesting approach to treating human retinal degenerations, but so far little quantitative data are available on possible beneficial effects. We isolated photoreceptor layers from normal-sighted mice and grafted them into the subretinal space of retinal degeneration (rd) mice lacking rod photoreceptors. At 2 weeks after surgery, the numbers of residual host cone photoreceptors outside the graft zone were quantified following specific labelling. Examination of operated retinas revealed highly significantly greater numbers of surviving cones (mean of 38% more at 2 weeks) within the central field compared to sham-operated paired control retinas (p < 0.01). These are the first quantified data indicating a trophic effect of transplanted photoreceptors upon host cone cells. As cone cells are responsible for high acuity and colour vision, such data could have important implications not only for eventual therapeutic approaches to human retinal degenerations but also to understanding underlying interactions between retinal photoreceptors.