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NRL is a transcription factor required for the specification and homeostasis of mammalian rod photoreceptors. In Nrl-deficient mice, photoreceptor precursor cells do not differentiate into rods, and instead follow a default photoreceptor specification pathway to generate S-cone-like cells. To investigate whether this genetic switch mechanism is conserved in humans, we used CRISPR\/Cas9 gene editing to engineer an NRL-deficient embryonic stem cell (ESC) line (NRL\u2212\/\u2212), and differentiated it into retinal organoids. Retinal organoids self-organize and resemble embryonic optic vesicles (OVs) that recapitulate the natural histogenesis of rods and cone photoreceptors. NRL\u2212\/\u2212 OVs develop comparably to controls, and exhibit a laminated, organized retinal structure with markers of photoreceptor synaptogenesis. Using immunohistochemistry and quantitative polymerase chain reaction (qPCR), we observed that NRL\u2212\/\u2212 OVs do not express NRL, or other rod photoreceptor markers directly or indirectly regulated by NRL. On the contrary, they show an abnormal number of photoreceptors positive for S-OPSIN, which define a primordial subtype of cone, and overexpress other cone genes indicating a conserved molecular switch in mammals. This study represents the first evidence in a human in\u2009vitro ESC-derived organoid system that NRL is required to define rod identity, and that in its absence S-cone-like cells develop as the default photoreceptor cell type. It shows how gene edited retinal organoids provide a useful system to investigate human photoreceptor specification, relevant for efforts to generate cells for transplantation in retinal degenerative diseases.<\/jats:p>","DOI":"10.1002\/stem.3325","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T10:00:26Z","timestamp":1611136826000},"page":"414-428","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["<i>NRL<\/i>\n                    \u2212\/\u2212 gene edited human embryonic stem cells generate rod-deficient retinal organoids enriched in S-cone-like photoreceptors"],"prefix":"10.1093","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9015-6572","authenticated-orcid":false,"given":"Elisa","family":"Cuevas","sequence":"first","affiliation":[{"name":"UCL Great Ormond Street Institute of Child Health, University College London and NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8532-6525","authenticated-orcid":false,"given":"Daniel L.","family":"Holder","sequence":"additional","affiliation":[{"name":"UCL Great Ormond Street Institute of Child Health, University College London and NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwak H.","family":"Alshehri","sequence":"additional","affiliation":[{"name":"UCL Great Ormond Street Institute of Child Health, University College London and NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Tr\u00e9guier","sequence":"additional","affiliation":[{"name":"UCL Great Ormond Street Institute of Child Health, University College London and NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rn","family":"Lakowski","sequence":"additional","affiliation":[{"name":"UCL Great Ormond Street Institute of Child Health, University College London and NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK"},{"name":"Centre for Human Development, Stem Cells and Regeneration, University of Southampton, Southampton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0937-2479","authenticated-orcid":false,"given":"Jane C.","family":"Sowden","sequence":"additional","affiliation":[{"name":"UCL Great Ormond Street Institute of Child Health, University College London and NIHR Great Ormond Street Hospital Biomedical Research Centre, London, 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