Cytosolic heat shock protein 90 is required for photoreceptor outer segment development and vision

Protein chaperones, such as heat shock protein 90 (HSP90), play essential roles in proteostasis by stabilizing client proteins and facilitating proper folding. Evidence for HSP90 function in vision is substantiated by reports of visual disturbances in patients treated with pan-HSP90 inhibitors. Among the cytosolic HSP90 paralogs, loss of HSP90α permits normal photoreceptor development, outer segment (OS) morphogenesis, and function, but rods subsequently undergo progressive degeneration despite upregulation of the closely related paralog HSP90β. In contrast, cone function is preserved in the absence of HSP90α, raising the question of whether cytosolic HSP90 paralogs have redundant functions or display functional specialization between rods and cones. To address this question, we generated a conditional KO of HSP90β (Hsp90ab1), which revealed that loss of HSP90β alone does not disrupt photoreceptor development, morphology, or visual function. In contrast, cone-specific ablation of both cytosolic paralogs resulted in rapid loss of cone function, demonstrating a shared requirement for cytosolic HSP90 activity in cones. To examine potential redundancy during development, we generated mice with targeted deletion of both cytosolic HSP90 paralogs within the photoreceptor lineage. Although retinal lamination was preserved, photoreceptors failed to elaborate OS, and visual responses were abolished. The severe visual phenotype correlated with reduced levels of peripherin, a protein essential for OS morphogenesis. Together, the findings define stage- and cell type-specific requirements for cytosolic HSP90 paralogs in the retina and establish a central role for cytosolic HSP90 in photoreceptor OS development and function.