{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:25:49Z","timestamp":1791606349017,"version":"4.3.4"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T00:00:00Z","timestamp":1595894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY025718"],"award-info":[{"award-number":["R01EY025718"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY015518"],"award-info":[{"award-number":["R01EY015518"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Children\u2019s Research Institute Foundation"},{"DOI":"10.13039\/100006645","name":"Children's Hospital of Wisconsin","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006645","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Advancing a Healthier Wisconsin","award":["#5520519"],"award-info":[{"award-number":["#5520519"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The Forkhead Box C1 (FOXC1) gene encodes a forkhead\/winged helix transcription factor involved in embryonic development. Mutations in this gene cause dysgenesis of the anterior segment of the eye, most commonly Axenfeld-Rieger syndrome (ARS), often with other systemic features. The developmental mechanisms and pathways regulated by FOXC1 remain largely unknown. There are two conserved orthologs of FOXC1 in zebrafish, foxc1a and foxc1b. To further examine the role of FOXC1 in vertebrates, we generated foxc1a and foxc1b single knockout zebrafish lines and bred them to obtain various allelic combinations. Three genotypes demonstrated visible phenotypes: foxc1a\u2212\/\u2212 single homozygous and foxc1\u2212\/\u2212 double knockout homozygous embryos presented with similar characteristics comprised of severe global vascular defects and early lethality, as well as microphthalmia, periocular edema and absence of the anterior chamber of the eye; additionally, fish with heterozygous loss of foxc1a combined with homozygosity for foxc1b (foxc1a+\/\u2212;foxc1b\u2212\/\u2212) demonstrated craniofacial defects, heart anomalies and scoliosis. All other single and combined genotypes appeared normal. Analysis of foxc1 expression detected a significant increase in foxc1a levels in homozygous and heterozygous mutant eyes, suggesting a mechanism for foxc1a upregulation when its function is compromised; interestingly, the expression of another ARS-associated gene, pitx2, was responsive to the estimated level of wild-type Foxc1a, indicating a possible role for this protein in the regulation of pitx2 expression. Altogether, our results support a conserved role for foxc1 in the formation of many organs, consistent with the features observed in human patients, and highlight the importance of correct FOXC1\/foxc1 dosage for vertebrate development.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa163","type":"journal-article","created":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T11:25:49Z","timestamp":1595589949000},"page":"2723-2735","source":"Crossref","is-referenced-by-count":22,"title":["Disruption of foxc1 genes in zebrafish results in dosage-dependent phenotypes overlapping Axenfeld-Rieger syndrome"],"prefix":"10.1093","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9511-2894","authenticated-orcid":false,"given":"Jes\u00fas-Jos\u00e9","family":"Ferre-Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena A","family":"Sorokina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross F","family":"Collery","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Nordquist","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Lincoln","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Division of Pediatric Cardiology, Herma Heart Institute, Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena V","family":"Semina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,28]]},"reference":[{"key":"2020110419230856400_ref1","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1038\/ejhg.2012.80","article-title":"PITX2 and FOXC1 spectrum of mutations in ocular syndromes","volume":"20","author":"Reis","year":"2012","journal-title":"Eur. 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