The orphan nuclear hormone receptor ERR controls rod photoreceptor survival.

Mutation of rod photoreceptor-enriched transcription factors is a major cause of inherited blindness. We identified the orphan nuclear hormone receptor ERR as selectively expressed in rod photoreceptors. Overexpression of ERR induces expression of rod-specific genes in retinas of both wildtype and in Nrl-/- mice, which lack rod photoreceptors. Mutation of ERR results in dysfunction and degeneration of rods, while inverse agonists of ERR trigger rapid rod degeneration, which is rescued by constitutively active mutants of ERR. ERR coordinates expression of multiple genes that are rate-limiting regulators of ATP generation and consumption in photoreceptors. Furthermore, enhancing ERR activity rescues photoreceptor defects that result from loss of the photoreceptor-specific transcription factor Crx. Our findings demonstrate that ERR is a critical regulator of rod photoreceptor function and survival, and suggest that ERR agonists may be useful in the treatment of certain retinal dystrophies.

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