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Otx2 expression is complex and underlies multiple cell fate decisions during development. To understand how Otx2 expression is regulated, we explored the activity and function of three of its enhancers (DHS2, DHS4 and DHS15). Enhancer reporter assays and lineage tracing show that DHS4 initiates Otx2 expression while DHS2 and DHS15 maintain expression in photoreceptors. Matched CRISPR\/Cas9 and CRISPR interference systems were used to mutate or epigenetically silence enhancers, respectively. CRISPR reduced OTX2 expression acutely, but failed to significantly alter cell fate choice over the long term. In contrast, CRISPR interference of these enhancers caused permanent OTX2 loss and corresponding cell fate changes. While these data suggest that each enhancer is needed for normal Otx2 expression, it also highlights that the enhancers can interact and substitute for each other during development. This cis-regulatory element flexibility likely promotes Otx2 expression robustness. Such robustness may enable complex genes, like Otx2, to resist environmental stressors and regulatory disruptions to promote reproducible developmental outcomes.<\/jats:p>","DOI":"10.1242\/dev.204881","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T08:37:53Z","timestamp":1772008673000},"source":"Crossref","is-referenced-by-count":0,"title":["A robust\n                    <i>cis<\/i>\n                    -regulatory network ensures\n                    <i>Otx2<\/i>\n                    expression during retinal development"],"prefix":"10.1242","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6960-6324","authenticated-orcid":false,"given":"Ian J.","family":"Purvis","sequence":"first","affiliation":[{"name":"University of Colorado Anschutz Medical Campus 1 Department of Ophthalmology , , Aurora, CO 80045 ,","place":["USA"]},{"name":"University of Colorado Anschutz Medical Campus 2 Cell Biology, Stem Cells, and Development Graduate Program , , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2931-3062","authenticated-orcid":false,"given":"Omar E.","family":"Ochoa Olmos","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus 1 Department of Ophthalmology , , Aurora, CO 80045 ,","place":["USA"]},{"name":"University of Colorado Anschutz Medical Campus 2 Cell Biology, Stem Cells, and Development Graduate Program , , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8254-5826","authenticated-orcid":false,"given":"Ko Uoon","family":"Park","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus 1 Department of Ophthalmology , , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2441-5836","authenticated-orcid":false,"given":"Michael L.","family":"Kaufman","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus 1 Department of Ophthalmology , , Aurora, CO 80045 ,","place":["USA"]},{"name":"University of Colorado Anschutz Medical Campus 3 Department of Biomedical Informatics , , Aurora, CO 80045 ,","place":["USA"]},{"name":"University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus 4 , Aurora, Colorado 80045 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7143-6055","authenticated-orcid":false,"given":"Charles M.","family":"Henry","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus 1 Department of Ophthalmology , , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7618-1547","authenticated-orcid":false,"given":"Chris","family":"Schaaf","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus 1 Department of Ophthalmology , , Aurora, CO 80045 ,","place":["USA"]},{"name":"University of Colorado Anschutz Medical Campus 2 Cell Biology, Stem Cells, and Development Graduate Program , , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia J.","family":"Clise","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus 1 Department of Ophthalmology , , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9572-2123","authenticated-orcid":false,"given":"Corey D.","family":"Tesdahl","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus 1 Department of Ophthalmology , , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9815-8954","authenticated-orcid":false,"given":"Ami","family":"Haas","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus 1 Department of Ophthalmology , , Aurora, CO 80045 ,","place":["USA"]},{"name":"University of Colorado Anschutz Medical Campus 5 Neurosciences Graduate Program , , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5854-0315","authenticated-orcid":false,"suffix":"IV","given":"Joseph A.","family":"Brzezinski","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus 1 Department of Ophthalmology , , Aurora, CO 80045 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