色素性视网膜炎
视网膜变性
视觉光转导
生物
基因剔除小鼠
视网膜
视紫红质
转基因
细胞生物学
神经保护
人类视网膜的基因治疗
遗传学
神经科学
视网膜
基因
生物化学
作者
Alexander V. Kolesnikov,Daniel Murphy,Joseph C. Corbo,Vladimir J. Kefalov
标识
DOI:10.1073/pnas.2316118121
摘要
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.
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