Role of the pigment epithelium in inherited retinal degeneration analyzed with experimental mouse chimeras

Abstract

In the study of inherited photoreceptor cell degenerations, a difficult problem is to determine the site of the primary genetic defect. It could be either intrinsic to the photoreceptor cells, the pigment epithelial cells or both, or extrinsic to these cells or to the eye as a whole. This problem was studied in mice with inherited retinal degeneration ( rd rd ) by analyzing the interaction of mutant and normal pigment epithelium with the underlying normal or degenerated retina in the eyes of experimental chimeric mice. Chimeras were produced by fusing eight-cell embryos of albino SJL ( rd rd ) mice with those of pigmented C57BL 10 (+/+) mice. The eyes of the resulting chimeric mice at 1·5–26·5 months of age had patches of normal retina interspersed with patches lacking photoreceptor cells. Pigment epithelial cells of both normal and mutant strains, identified by the presence or absence of melanosomes, were found overlying areas of both normal and degenerated retina. The same findings were obtained using two other strain combinations, C3H (pigmented, rd rd ) fused with BALB c (albino, +/+) and SJL (albino, rd rd ) fused with C57BL 10 × CBA F 1 hybrids (pigmented, +/rd). The synthesis of rod outer segment dises proceeded normally in photoreceptor cells underlying mutant pigment epithelial cells, as determined by autoradiographic analysis, and phagosomes were found in both mutant and normal pigment epithelial cells. The findings indicate that the pigment epithelial cell is not the primary target of the mutant rd gene in the mouse and localize the site of mutant gene action to the neural retina, presumably but not necessarily, to the photoreceptor cells.