Department de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Barcelona 08028, Spain; IBUB-IRSJD, Institut de Biomedicina de la Universitat de Barcelona-Institut de Recerca Sant Joan de Déu, Barcelona 08028, Spain; CIBERER, Instituto de Salud Carlos III, Barcelona 08028, Spain.
Max-Planck-Institute for Molecular Biomedicine, Münster 48149, Germany.
Neurobiol Dis. 2024 May;194:106463. doi: 10.1016/j.nbd.2024.106463. Epub 2024 Mar 12.
Mutations in NR2E3, a gene encoding an orphan nuclear transcription factor, cause two retinal dystrophies with a distinct phenotype, but the precise role of NR2E3 in rod and cone transcriptional networks remains unclear. To dissect NR2E3 function, we performed scRNA-seq in the retinas of wildtype and two different Nr2e3 mouse models that show phenotypes similar to patients carrying NR2E3 mutations. Our results reveal that rod and cone populations are not homogeneous and can be separated into different sub-classes. We identify a previously unreported cone pathway that generates hybrid cones co-expressing both cone- and rod-related genes. In mutant retinas, this hybrid cone subpopulation is more abundant and includes a subpopulation of rods transitioning towards a cone cell fate. Hybrid photoreceptors with high misexpression of cone- and rod-related genes are prone to regulated necrosis. Overall, our results shed light on the role of NR2E3 in modulating photoreceptor differentiation towards cone and rod fates and explain how different mutations in NR2E3 lead to distinct visual disorders in humans.
NR2E3 基因突变，该基因编码一种孤儿核转录因子，导致两种具有明显表型的视网膜营养不良，但 NR2E3 在视杆和视锥转录网络中的确切作用仍不清楚。为了剖析 NR2E3 的功能，我们在野生型和两种不同 Nr2e3 小鼠模型的视网膜中进行了 scRNA-seq 分析，这两种小鼠模型的表型与携带 NR2E3 突变的患者相似。我们的结果表明，视杆和视锥细胞群体不是同质的，可以分为不同的亚类。我们鉴定出一种以前未报道的视锥细胞途径，该途径产生同时表达视锥细胞和视杆细胞相关基因的混合视锥细胞。在突变的视网膜中，这种混合视锥细胞亚群更为丰富，包括向视锥细胞命运转变的视杆细胞亚群。高表达视锥细胞和视杆细胞相关基因的混合光感受器易发生受调控的坏死。总的来说，我们的研究结果揭示了 NR2E3 在调节光感受器向视锥细胞和视杆细胞命运分化中的作用，并解释了 NR2E3 中的不同突变如何导致人类出现不同的视觉障碍。
