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Volume 12
Issue 2
10.3390/genes12020170
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Article

The Axenfeld–Rieger Syndrome Gene FOXC1 Contributes to Left–Right Patterning

by
Paul W. Chrystal
1,2,3,
Curtis R. French
1,2,4,
Francesca Jean
3,
Serhiy Havrylov
1,2,
Suey van Baarle
1,2,
Ann-Marie Peturson
3,
Pengfei Xu
5,
J. Gage Crump
5,
David B. Pilgrim
3,6,
Ordan J. Lehmann
1,2,6,* and
Andrew J. Waskiewicz
3,6,*
1
Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada
2
Department of Ophthalmology, University of Alberta, Edmonton, AB T6G 2H7, Canada
3
Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
4
Faculty of Medicine, Memorial University of Newfoundland, St John’s, NL A1B 3V6, Canada
5
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
6
Women & Children’s Health Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
*
Authors to whom correspondence should be addressed.
Genes 2021, 12(2), 170; https://doi.org/10.3390/genes12020170
Received: 24 December 2020 / Revised: 14 January 2021 / Accepted: 21 January 2021 / Published: 26 January 2021
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Abstract

Precise spatiotemporal expression of the Nodal-Lefty-Pitx2 cascade in the lateral plate mesoderm establishes the left–right 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–Rieger syndrome (ARS). Since cardiac involvement is an established ARS phenotype and because disrupted left–right 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−/−; foxc1b−/− 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–right 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–right 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–Rieger syndrome patients. View Full-Text
Keywords: FOXC1; Axenfeld–Rieger syndrome; left–right patterning; zebrafish; LEFTY FOXC1; Axenfeld–Rieger syndrome; left–right patterning; zebrafish; LEFTY
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MDPI and ACS Style

Chrystal, P.W.; French, C.R.; Jean, F.; Havrylov, S.; van Baarle, S.; Peturson, A.-M.; Xu, P.; Crump, J.G.; Pilgrim, D.B.; Lehmann, O.J.; Waskiewicz, A.J. The Axenfeld–Rieger Syndrome Gene FOXC1 Contributes to Left–Right Patterning. Genes 2021, 12, 170. https://doi.org/10.3390/genes12020170

AMA Style

Chrystal PW, French CR, Jean F, Havrylov S, van Baarle S, Peturson A-M, Xu P, Crump JG, Pilgrim DB, Lehmann OJ, Waskiewicz AJ. The Axenfeld–Rieger Syndrome Gene FOXC1 Contributes to Left–Right Patterning. Genes. 2021; 12(2):170. https://doi.org/10.3390/genes12020170

Chicago/Turabian Style

Chrystal, Paul W., Curtis R. French, Francesca Jean, Serhiy Havrylov, Suey van Baarle, Ann-Marie Peturson, Pengfei Xu, J. G. Crump, David B. Pilgrim, Ordan J. Lehmann, and Andrew J. Waskiewicz. 2021. "The Axenfeld–Rieger Syndrome Gene FOXC1 Contributes to Left–Right Patterning" Genes 12, no. 2: 170. https://doi.org/10.3390/genes12020170

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