The orphan nuclear hormone receptor ERRbeta 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 estrogen-related receptor beta (ERRbeta) as selectively expressed in rod photoreceptors. Overexpression of ERRbeta induces expression of rod-specific genes in retinas of wild-type as well as Nrl(-/-) mice, which lack rod photoreceptors. Mutation of ERRbeta results in dysfunction and degeneration of rods, whereas inverse agonists of ERRbeta trigger rapid rod degeneration, which is rescued by constitutively active mutants of ERRbeta. ERRbeta coordinates expression of multiple genes that are rate-limiting regulators of ATP generation and consumption in photoreceptors. Furthermore, enhancing ERRbeta activity rescues photoreceptor defects that result from loss of the photoreceptor-specific transcription factor Crx. Our findings demonstrate that ERRbeta is a critical regulator of rod photoreceptor function and survival, and suggest that ERRbeta agonists may be useful in the treatment of certain retinal dystrophies.
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Akishi
A
Onishi
Guang-Hua
GH
Peng
Erin M
EM
Poth
Daniel A
DA
Lee
Jichao
J
Chen
Uel
U
Alexis
Jimmy
J
de Melo
Shiming
S
Chen
Seth
S
Blackshaw
D000818:Animals; D002470:Cell Survival; D004596:Electroretinography / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011960:Receptors, Estrogen / Q000378:metabolism*; D012160:Retina / Q000196:embryology* / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012243:Rhodopsin / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*
D018398:Homeodomain Proteins; D008024:Ligands; D011960:Receptors, Estrogen; D015534:Trans-Activators; C109288:cone rod homeobox protein; C107914:estrogen receptor-related receptor beta; D012243:Rhodopsin