RPE dysplasia with retinal duplication in a mutant mouse strain

An autosomal dominant mutation was produced by quadruple gonadal exposure of a male (C3H x 101)F1 mouse to 500 rad of X-irradiation. This mutation is maintained by the mating of affected heterozygous males to normal (C3H x C57B1)F1 females. Clinically apparent abnormalities were limited to the eyes and, in the affected adults, ranged from apparent anophthalmia to globes that were enlarged and exhibit large uveoscleral colobomas. Sequential evaluations of the embryogenesis of this condition have identified abnormal differentiation of the outer layer of the optic cup (presumptive retinal pigment epithelium-RPE) into a second layer of neural retina. The abnormality is identified as early as day 10 of gestation, during invagination of the optic cup and lens placode. The area of RPE dysplasia may be diffuse or regional with an abrupt transition from normal RPE and often demonstrates excessive and uncontrolled proliferation. The two symmetrical, apposed layers of photoreceptors fail to differentiate and begin to degenerate prenatally. Absence of normal RPE leads to failure of induction of adjacent choroid and sclera, resulting in a posterior segment consisting of a large neuroepithelial-lined cyst. Radiation-induced ocular malformations of this type have not been previously described. In addition, this model presents a unique opportunity to examine the processes leading to differentiation of a single, continuous epithelial layer into tissues as anatomically and functionally distinct as neural retina and RPE.