The orphan nuclear hormone receptor ERRβ 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 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. 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.

杆状感光细胞富集的转录因子突变是遗传性失明的主要致病诱因。我们鉴定出孤儿核激素受体ERRβ(orphan nuclear hormone receptor ERRβ)在杆状感光细胞中呈特异性表达。过表达ERRβ可在野生型及缺乏杆状感光细胞的Nrl-/-小鼠的视网膜中诱导杆状特异性基因的表达。ERRβ突变会导致杆状感光细胞功能异常与退行性病变，而ERRβ的反向激动剂可触发杆状感光细胞快速退行，该表型可通过组成型激活的ERRβ突变体得以挽救。ERRβ可协同调控感光细胞内ATP生成与消耗的多个限速调控基因的表达。此外，增强ERRβ的活性可挽救因感光细胞特异性转录因子Crx缺失所引发的感光细胞功能缺陷。本研究结果证实，ERRβ是调控杆状感光细胞功能与存活的关键调节因子，并提示ERRβ激动剂或可用于部分视网膜营养不良症的治疗。本研究采用Affymetrix MOE430微阵列(Affymetrix MOE430 microarrays)分析了出生后21日龄(P21)小鼠的视网膜组织表达谱，并以基因型为分组变量开展对比分析，具体比较了ERRβ敲除型与野生型小鼠的表达差异。