The cytoplasmic tail of rhodopsin triggers rapid rod degeneration in kinesin-2 mutants.

Photoreceptor degeneration can lead to blindness and represents the most common form of neural degenerative disease worldwide. Although many genes involved in photoreceptor degeneration have been identified, the underlying mechanisms remain to be elucidated. Here we examined photoreceptor development in zebrafish kif3a and kif3b mutants, which affect two subunits of the kinesin-2 complex. In both mutants, rods degenerated quickly, whereas cones underwent a slow degeneration process. Notably, the photoreceptor defects were considerably more severe in kif3a mutants than in kif3b mutants. In the cone photoreceptors of kif3a mutants, opsin proteins accumulated in the apical region and formed abnormal membrane structures. In contrast, rhodopsins were enriched in the rod cell body membrane and represented the primary reason for rapid rod degeneration in these mutants. Moreover, removal of the cytoplasmic tail of rhodopsin to reduce its function, but not decreasing rhodopsin expression levels, prevented rod degeneration in both kif3a and kif3b mutants. Of note, overexpression of full-length rhodopsin or its cytoplasmic tail domain, but not of rhodopsin lacking the cytoplasmic tail, exacerbated rod degeneration in kif3a mutants, implying an important role of the cytoplasmic tail in rod degeneration. Finally, we showed that the cytoplasmic tail of rhodopsin might trigger rod degeneration through activating the downstream calcium signaling pathway, as drug treatment with inhibitors of intracellular calcium release prevented rod degeneration in kif3a mutants. Our results demonstrate a previously unknown function of the rhodopsin cytoplasmic domain during opsin-triggered photoreceptor degeneration and may open up new avenues for managing this disease.