PDF(Pubmed)
Abstract：
Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting Nr2e3, a transcription factor required for the normal differentiation of rod photoreceptors. Nr2e3 knockout results in hybrid rod photoreceptors that express the full complement of rod genes, but also a subset of cone genes. We show that germline deletion of Nr2e3 potently protects rods in three mechanistically diverse mouse models of retinal degeneration caused by bright-light exposure (light damage), structural deficiency (rhodopsin-deficient Rho-/- mice), or abnormal phototransduction (phosphodiesterase-deficient rd10 mice). Nr2e3 knockout confers strong neuroprotective effects on rods without adverse effects on their gene expression, structure, or function. Furthermore, in all three degeneration models, prolongation of rod survival by Nr2e3 knockout leads to lasting preservation of cone morphology and function. These findings raise the possibility that upregulation of one or more cone genes in Nr2e3-deficient rods may be responsible for the neuroprotective effects we observe.
摘要：
色素性视网膜炎（RP）是视网膜营养不良的常见形式，可由数十种视杆感光基因中的任何一种突变引起。RP的遗传异质性代表了开发有效疗法的重大挑战。这里,我们提供了基于靶向Nr2e3的潜在基因非依赖性治疗策略的证据,Nr2e3是杆状光感受器正常分化所必需的转录因子.Nr2e3敲除导致杂交杆光感受器表达杆基因的完整互补，但也是视锥基因的一个子集。我们表明，Nr2e3的种系缺失可有效保护由强光暴露（光损伤）引起的三种机械不同的视网膜变性小鼠模型中的棒，结构缺陷（视紫红质缺陷型Rh-/-小鼠），或异常光转导（磷酸二酯酶缺乏的rd10小鼠）。Nr2e3基因敲除对杆具有强大的神经保护作用，对其基因表达没有不利影响。结构,或功能。此外，在所有三个退化模型中，通过Nr2e3敲除延长杆的存活会导致视锥形态和功能的持久保留。这些发现提高了Nr2e3缺陷杆中一个或多个视锥基因的上调可能是我们观察到的神经保护作用的原因。
