{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:35:06Z","timestamp":1781109306536,"version":"3.54.1"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"21","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["EY030075"],"award-info":[{"award-number":["EY030075"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["EY033810"],"award-info":[{"award-number":["EY033810"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["P30 EY034070"],"award-info":[{"award-number":["P30 EY034070"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Washington University's Hope Center for Neurological Disorders","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,5,27]]},"abstract":"<jats:p>\n                    Acute knockout of the rod photoreceptor transcription factor\n                    <jats:italic toggle=\"yes\">Nrl<\/jats:italic>\n                    delays retinal degeneration in multiple mouse models of blindness, but the downstream transcriptomic changes that mediate these therapeutic effects are unknown. Here, we show that acute\n                    <jats:italic toggle=\"yes\">Nrl<\/jats:italic>\n                    knockout causes upregulation of a subset of cone genes in rods as well as downregulation of rod genes, including the rod-specific transcriptional repressor\n                    <jats:italic toggle=\"yes\">Nr2e3<\/jats:italic>\n                    . We hypothesized that\n                    <jats:italic toggle=\"yes\">Nr2e3<\/jats:italic>\n                    downregulation might mediate some of the therapeutic effects of\n                    <jats:italic toggle=\"yes\">Nrl<\/jats:italic>\n                    knockout. Indeed, acute knockout of\n                    <jats:italic toggle=\"yes\">Nr2e3<\/jats:italic>\n                    prevents photoreceptor degeneration and preserves visual function in mice with mutations in the catalytic subunit of the rod-specific phosphodiesterase (\n                    <jats:italic toggle=\"yes\">\n                      Pde6b\n                      <jats:sup>rd10\/rd10<\/jats:sup>\n                    <\/jats:italic>\n                    ). Upregulation of\n                    <jats:italic toggle=\"yes\">Pde6c<\/jats:italic>\n                    , the cone-specific paralog of\n                    <jats:italic toggle=\"yes\">Pde6b<\/jats:italic>\n                    , in\n                    <jats:italic toggle=\"yes\">Nr2e3<\/jats:italic>\n                    -knockout rods is required to prevent degeneration in\n                    <jats:italic toggle=\"yes\">\n                      Pde6b\n                      <jats:sup>rd10\/rd10<\/jats:sup>\n                    <\/jats:italic>\n                    mice, suggesting that this therapeutic effect is mediated, at least in part, by a gene-replacement mechanism. In contrast, acute\n                    <jats:italic toggle=\"yes\">Nr2e3<\/jats:italic>\n                    knockout fails to prevent degeneration caused by loss- or gain-of-function mutations in Rhodopsin (\n                    <jats:italic toggle=\"yes\">\n                      Rho\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">\n                      Rho\n                      <jats:sup>P23H\/P23H<\/jats:sup>\n                    <\/jats:italic>\n                    ), whereas acute\n                    <jats:italic toggle=\"yes\">Nrl<\/jats:italic>\n                    knockout delays degeneration in both models. Surprisingly, the therapeutic effect of acute\n                    <jats:italic toggle=\"yes\">Nrl<\/jats:italic>\n                    knockout in\n                    <jats:italic toggle=\"yes\">\n                      Pde6b\n                      <jats:sup>rd10\/rd10<\/jats:sup>\n                    <\/jats:italic>\n                    mice does not depend on\n                    <jats:italic toggle=\"yes\">Pde6c<\/jats:italic>\n                    upregulation. These results suggest that acute\n                    <jats:italic toggle=\"yes\">Nrl<\/jats:italic>\n                    knockout may exert its therapeutic effects via a mechanism independent of\n                    <jats:italic toggle=\"yes\">Nr2e3<\/jats:italic>\n                    downregulation, perhaps by downregulating other rod genes. We conclude that acute\n                    <jats:italic toggle=\"yes\">NRL<\/jats:italic>\n                    knockout may be a promising gene-independent strategy for preventing photoreceptor degeneration in human patients.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2500446122","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T13:32:58Z","timestamp":1747834378000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Mechanisms of photoreceptor protection upon targeting the\n                    <i>Nrl\u2013Nr2e3<\/i>\n                    pathway"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4846-4608","authenticated-orcid":false,"given":"Daniel P.","family":"Murphy","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine","place":["St. Louis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander V.","family":"Kolesnikov","sequence":"additional","affiliation":[{"name":"Gavin Herbert Eye Institute, Department of Ophthalmology, University of California","place":["Irvine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia L.","family":"Montana","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine","place":["St. Louis"]},{"name":"Department of Ophthalmology, Washington University School of Medicine","place":["St. Louis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0101-1399","authenticated-orcid":false,"given":"Zaid M.","family":"Khaja","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine","place":["St. Louis"]},{"name":"Saint Louis University School of Medicine","place":["St. Louis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine","place":["St. Louis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1659-008X","authenticated-orcid":false,"given":"Vladimir J.","family":"Kefalov","sequence":"additional","affiliation":[{"name":"Gavin Herbert Eye Institute, Department of Ophthalmology, University of California","place":["Irvine"]},{"name":"Department of Physiology and Biophysics, University of California","place":["Irvine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9323-7140","authenticated-orcid":false,"given":"Joseph C.","family":"Corbo","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine","place":["St. 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