Genetic Loss of RORα Impairs Visual Function With Rod Bipolar Cell Degeneration In Mice.

Purpose: Retinoic acid receptor-related orphan receptor alpha (RORα) is a ligand-dependent nuclear receptor involved in eye development and diseases. Genetic variations of RORα have been linked with the development of age-related macular degeneration, yet whether RORα regulates visual function is unknown. In this study we investigated the role of RORα in regulating visual function in mice with genetic deficiency of RORα.

Methods: RORα deficient staggerer (Rorasg/sg) and age-matched wild type control mice were assessed for visual function using electroretinography (ERG). Retinal localization of RORα and rod bipolar cell morphology were assessed using immunohistochemistry. Retinal thickness was measured as well as presence of retinal gliosis, and expression of genes in visual transduction.

Results: RORα is expressed in photoreceptors, retinal ganglion cells, and bipolar cells. Genetic deletion of RORα in Rorasg/sg mice markedly impaired visual function measured by ERG, with substantial attenuation of b-wave amplitude compared with wild type controls, reflective of bipolar cell dysfunction. Rorasg/sg eyes showed significant degeneration of rod bipolar cells and retinal gliosis, both of which progressed upon aging. Moreover, loss of ROR⍺ also resulted in significant retinal thinning, including both outer and inner nuclear layers. Expression of genes involved in phototransduction and rod bipolar cell depolarization was upregulated in Rorasg/sg retinas, suggestive of potential compensatory remodeling of visual signaling.

Conclusions: Our findings demonstrate that RORα is indispensable for the structural and functional maintenance of rod bipolar cells and could pose as a potential therapeutic target for mitigating bipolar cell deficits in retinal degenerative diseases.