The orphan nuclear hormone receptor ERR β controls rod photoreceptor survival

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

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