{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:25:48Z","timestamp":1791606348961,"version":"4.3.4"},"reference-count":91,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T00:00:00Z","timestamp":1611619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002790","name":"Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN 2016-06482"],"award-info":[{"award-number":["RGPIN 2016-06482"]}],"id":[{"id":"10.13039\/501100002790","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DE027550"],"award-info":[{"award-number":["DE027550"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Precise spatiotemporal expression of the Nodal-Lefty-Pitx2 cascade in the lateral plate mesoderm establishes the left\u2013right axis, which provides vital cues for correct organ formation and function. Mutations of one cascade constituent PITX2 and, separately, the Forkhead transcription factor FOXC1 independently cause a multi-system disorder known as Axenfeld\u2013Rieger syndrome (ARS). Since cardiac involvement is an established ARS phenotype and because disrupted left\u2013right patterning can cause congenital heart defects, we investigated in zebrafish whether foxc1 contributes to organ laterality or situs. We demonstrate that CRISPR\/Cas9-generated foxc1a and foxc1b mutants exhibit abnormal cardiac looping and that the prevalence of cardiac situs defects is increased in foxc1a\u2212\/\u2212; foxc1b\u2212\/\u2212 homozygotes. Similarly, double homozygotes exhibit isomerism of the liver and pancreas, which are key features of abnormal gut situs. Placement of the asymmetric visceral organs relative to the midline was also perturbed by mRNA overexpression of foxc1a and foxc1b. In addition, an analysis of the left\u2013right patterning components, identified in the lateral plate mesoderm of foxc1 mutants, reduced or abolished the expression of the NODAL antagonist lefty2. Together, these data reveal a novel contribution from foxc1 to left\u2013right patterning, demonstrating that this role is sensitive to foxc1 gene dosage, and provide a plausible mechanism for the incidence of congenital heart defects in Axenfeld\u2013Rieger syndrome patients.<\/jats:p>","DOI":"10.3390\/genes12020170","type":"journal-article","created":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T23:01:28Z","timestamp":1611702088000},"page":"170","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Axenfeld\u2013Rieger Syndrome Gene FOXC1 Contributes to Left\u2013Right Patterning"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5371-1178","authenticated-orcid":false,"given":"Paul W.","family":"Chrystal","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada"},{"name":"Department of Ophthalmology, University of Alberta, Edmonton, AB T6G 2H7, Canada"},{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis R.","family":"French","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada"},{"name":"Department of Ophthalmology, University of Alberta, Edmonton, AB T6G 2H7, Canada"},{"name":"Faculty of Medicine, Memorial University of Newfoundland, St John\u2019s, NL A1B 3V6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Jean","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serhiy","family":"Havrylov","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada"},{"name":"Department of Ophthalmology, University of Alberta, Edmonton, AB T6G 2H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suey","family":"van Baarle","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada"},{"name":"Department of Ophthalmology, University of Alberta, Edmonton, AB T6G 2H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Marie","family":"Peturson","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Gage","family":"Crump","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Pilgrim","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"},{"name":"Women &amp; Children\u2019s Health Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4141-7411","authenticated-orcid":false,"given":"Ordan J.","family":"Lehmann","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada"},{"name":"Department of Ophthalmology, University of Alberta, Edmonton, AB T6G 2H7, Canada"},{"name":"Women &amp; Children\u2019s Health Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5306-0643","authenticated-orcid":false,"given":"Andrew J.","family":"Waskiewicz","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"},{"name":"Women &amp; Children\u2019s Health Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.ejmg.2005.12.003","article-title":"Human laterality disorders","volume":"49","author":"Peeters","year":"2006","journal-title":"Eur. 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