The orphan nuclear hormone receptor ERRβ controls rod photoreceptor survival.. Mus musculus

Mutation of rod photoreceptor-enriched transcription factors is a major cause of inherited blindness. We identified the orphan nuclear hormone receptor ERRβ as selectively expressed in rod photoreceptors. Overexpression of ERRβ induces expression of rod-specific genes in retinas of both wildtype and in Nrl-/- mice, which lack rod photoreceptors. Mutation of ERRβ results in dysfunction and degeneration of rods, while inverse agonists of ERRβ trigger rapid rod degeneration, which is rescued by constitutively active mutants of ERRβ. ERRβ coordinates expression of multiple genes that are rate-limiting regulators of ATP generation and consumption in photoreceptors. Furthermore, enhancing ERRβ activity rescues photoreceptor defects that result from loss of the photoreceptor-specific transcription factor Crx. Our findings demonstrate that ERRβ is a critical regulator of rod photoreceptor function and survival, and suggest that ERRβ agonists may be useful in the treatment of certain retinal dystrophies. Overall design: Affymetrix MOE430 microarrays were used to analyze the expression patterns of P21 mouse retinal tissues. The results were compared across the variable of Genotype, specifically ERRβ knockout versus wildtype.

富集于视杆细胞的转录因子突变是遗传性失明的主要诱因。我们鉴定出孤儿核激素受体（orphan nuclear hormone receptor）ERRβ选择性表达于视杆细胞中。ERRβ过表达可在野生型及缺乏视杆细胞的Nrl基因敲除（Nrl-/-）小鼠的视网膜中诱导视杆细胞特异性基因的表达。ERRβ突变会导致视杆细胞功能异常与退行性变，而ERRβ反向激动剂可引发视杆细胞快速退行性变，该表型可被ERRβ组成型活性突变体挽救。ERRβ可协调调控感光细胞中作为ATP生成与消耗限速调控因子的多个基因的表达。此外，增强ERRβ活性可挽救因感光细胞特异性转录因子Crx缺失所导致的感光细胞缺陷。本研究结果证实ERRβ是调控视杆细胞功能与存活的关键因子，并提示ERRβ激动剂或可用于治疗部分视网膜营养不良症。实验设计：采用Affymetrix MOE430基因芯片分析P21小鼠视网膜组织的表达模式，以基因型为变量（即ERRβ敲除小鼠与野生型小鼠）进行结果比对。