{"doi":"10.1101/2023.06.30.547279","title":"Loss of NR2E3 disrupts rod photoreceptor cell maturation causing a fate switch late in human retinal development","abstract":"ABSTRACT While dysfunction and death of light-detecting photoreceptor cells underlie most inherited retinal dystrophies, knowledge of the species-specific details of human rod and cone photoreceptor cell development remains limited. Here, we generate retinal organoids using induced pluripotent stem cells (iPSC) derived from a patient with genetic photoreceptor disease due to mutations in NR2E3 , an isogenic control, and an unrelated control. Organoids were sampled using single-cell RNA sequencing across the developmental window encompassing photoreceptor specification, emergence, and maturation, up to 260 days of in vitro differentiation. Using single-cell transcriptomics data, we reconstruct the rod photoreceptor developmental lineage and identify a branchpoint in development unique to the disease state that gives rise to a divergent rod photoreceptor cell population. We show that the rod-specific transcription factor NR2E3 is required for the proper expression of genes involved in phototransduction, including expression of the light-sensitive protein rhodopsin, which is absent in divergent rods. NR2E3-null rods additionally misexpress several cone-specific phototransduction genes at both the transcript and protein level. Using joint multimodal single-cell sequencing on late-stage retinal organoids, we further identify specific putative regulatory sites where rod-specific factors act to steer rod and cone photoreceptor cell development. Importantly, these findings are strikingly different than those observed in rodent models of disease. Together, these data provide a roadmap of human photoreceptor development and leverage patient iPSCs to define the specific roles of rod transcription factors in photoreceptor cell emergence and maturation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":393431,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9461,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":365434,"name":"Laura R. Bohrer","orcid":null,"position":1,"is_corresponding":false},{"id":270475,"name":"Andrew P. Voigt","orcid":"0000-0001-8107-8317","position":2,"is_corresponding":false},{"id":880968,"name":"Lola Lozano","orcid":"0000-0002-0492-4759","position":3,"is_corresponding":false},{"id":1099218,"name":"Allison T. Wright","orcid":null,"position":4,"is_corresponding":false},{"id":270480,"name":"Robert F. Mullins","orcid":"0000-0002-5006-0891","position":5,"is_corresponding":false},{"id":270479,"name":"Edwin M. Stone","orcid":"0000-0003-3343-4414","position":6,"is_corresponding":false},{"id":270478,"name":"Budd A. Tucker","orcid":"0000-0003-2178-1742","position":7,"is_corresponding":false},{"id":363972,"name":"Nathaniel K. Mullin","orcid":"0000-0003-4320-2852","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T01:19:05.913428Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}