Germline knockout of Nr2e3 protects photoreceptors in three distinct mouse models of retinal degeneration

• 成果类型: Article
• 署名作者: Kolesnikov, Alexander V.; Murphy, Daniel P.; Corbo, Joseph C.; Kefalov, Vladimir J.
• 署名单位: University of California System; University of California Irvine; Washington University (WUSTL)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13978
• DOI: 10.1073/pnas.2316118121
• 发表日期: 2024-03-05
• 关键词: rod photoreceptors; gene-therapy; cone; nrl; mutations; vision; mice; transcription; features; adult

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 heteroge-neity of RP represents a significant challenge for the development of effective thera-pies. Here, we present evidence for a potential gene- independent therapeutic strategy based on targeting Nr2e3, a transcription factor required for the normal differentia-tion 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 Nr2e3knockout 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. SignificanceRetinitis pigmentosa (RP) is a common form of retinal degenerative disease 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 gene encoding a transcription factor required for the normal differentiation of rod photoreceptors. Nr2e3- deficient mouse rods express the normal complement of rod photoreceptor genes but also a subset of cone genes. We show that Nr2e3- deficient rods are remarkably resistant to degeneration in three mechanistically diverse RP models, suggesting that the upregulation of cone genes in Nr2e3- deficient rods has a strong neuroprotective effect.