Mdm1 ablation results in retinal degeneration by specific intraflagellar transport defects of photoreceptor cells.

ABSTRACT

Mouse double minute 1 (Mdm1) might be involved in the function and structure of centrioles and age-related retinal degeneration. However, the mechanism by which Mdm1 deficiency causes retinal degeneration remains unknown. We confirmed that the Mdm1 protein is localized at the connecting cilium (CC) of photoreceptor cells in the retina. The electroretinograms of 6-week-old Mdm1-/- mice revealed decreased vision, which was eventually lost, and outer segment (OS) photoreceptor degeneration was evident on postnatal day 7, with complete loss of the outer nuclear layer (ONL) observed at 35 weeks. Mdm1-/- mouse retinas showed mislocalization of opsins in the photoreceptor cells, indicating particular intraflagellar transport (IFT) defects, and entrapment of the nuclei in the ONL by microvilli of retinal pigment epithelial cells, leading to apoptosis in the ONL. These results suggest that Mdm1 ablation causes specific IFT defects, which prevents the OS from continuously replenishing new discs, resulting in retinal degeneration.