Specific photoreceptor cell fate pathways are differentially altered in NR2E3-associated diseases

SUMMARY Mutations in NR2E3 cause two retinal dystrophies with a distinct phenotype. NR2E3 encodes an orphan nuclear transcription factor that contributes to photoreceptor cell fate determination by repressing cone while activating rod genes. To dissect NR2E3 function, we performed scRNA-seq in the retinas of wild type 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 that co-express both cone- and rod-related genes. In mutant retinas, this hybrid cone subpopulation is more abundant, as it 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 mutations in NR2E3 lead to different visual disorders in humans. GRAPHICAL ABSTRACT SYNOPSIS Mutations in the gene encoding the retinal transcription factor NR2E3 cause two different inherited retinal dystrophies: retinitis pigmentosa and enhanced S-cone syndrome. scRNA-seq in retinas of wild type and two Nr2e3 mouse models reveal that rod and cone populations are not homogeneous and can be classified into different sub-classes. A previously unreported cone pathway that generates hybrid cones co- expressing both cone- and rod-related genes is identified. Hybrid photoreceptors with high misexpression of cone- and rod-related genes are prone to regulated necrosis. Expression of rod and cone signature genes change in response to different NR2E3 mutations thus providing a frame to understand the molecular basis of distinct NR2E3-associated diseases.