Mutation of rod photoreceptor-enriched transcription factors is a major cause of inherited blindness. We identified the orphan nuclear hormone receptor estrogen-related receptor Ī² (ERRĪ²) as selectively expressed in rod photoreceptors. Overexpression of ERRĪ² induces expression of rod-specific genes in retinas of wild-type as well as Nrl ā/ā mice, which lack rod photoreceptors. Mutation of ERRĪ² results in dysfunction and degeneration of rods, whereas inverse agonists of ERRĪ² trigger rapid rod degeneration, which is rescued by constitutively active mutants of ERRĪ². ERRĪ² coordinates expression of multiple genes that are rate-limiting regulators of ATP generation and consumption in photoreceptors. Furthermore, enhancing ERRĪ² activity rescues photoreceptor defects that result from loss of the photoreceptor-specific transcription factor Crx. Our findings demonstrate that ERRĪ² is a critical regulator of rod photoreceptor function and survival, and suggest that ERRĪ² agonists may be useful in the treatment of certain retinal dystrophies.T he vertebrate retina contains two major subtypes of photoreceptors-rods and cones. Clinically, dysfunction and death of rod photoreceptors are the primary causes of most forms of inherited photoreceptor dystrophy. A number of rod-expressed transcription factors (1-7) have been identified that are required for rod photoreceptor differentiation or survival. Biochemical analysis has indicated that these factors are present at the promoters of rod-specific genes in vivo and directly activate expression of rod-specific genes (1,8,9). Mutation of rod-enriched transcription factors in humans can lead to rod photoreceptor dystrophy (10, 11). Failure to express normal levels of rodspecific genes thus results in rod photoreceptor degeneration, and correction of this defect may have considerable value in treating inherited blindness.Analysis of gene expression in developing and mature rod photoreceptors has indicated that other transcription factors also show highly rod-enriched expression (12-15). Among these is estrogen-related receptor Ī² (ERRĪ²), an orphan nuclear hormone receptor homologous to the classical estrogen receptor but which constitutively activates transcription in the absence of estradiol (16,17). ERRĪ² is specifically expressed in differentiating and mature mouse rod photoreceptors (12, 13), with significant mRNA levels also detected in the human retina (18). Deletion of a floxed allele of ERRĪ² in the embryoid body using a Sox2-Cre line (hereafter referred to as ERRĪ² ā/ā ) results in mice with a defect in inner ear development but no obvious retinal defects (19). Loss-of-function mutations of ERRĪ² have been reported in inherited forms of human deafness (20).Given the prominent expression of ERRĪ² in retinal photoreceptors, we hypothesized that ERRĪ² might also play an important role in rod photoreceptor function. We observed that genetic or pharmacological disruption of function of ERRĪ² leads to rod photoreceptor degeneration. ERRĪ² also directly regulates expression of rod-specific gen...