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

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 ...

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Main Authors:	Paul W. Chrystal, Curtis R. French, Francesca Jean, Serhiy Havrylov, Suey van Baarle, Ann-Marie Peturson, Pengfei Xu, J. Gage Crump, David B. Pilgrim, Ordan J. Lehmann, Andrew J. Waskiewicz
Format:	Article
Language:	English
Published:	MDPI AG 2021-01-01
Series:	Genes
Subjects:	<i>FOXC1</i> Axenfeld–Rieger syndrome left–right patterning zebrafish <i>LEFTY</i>
Online Access:	https://www.mdpi.com/2073-4425/12/2/170

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record_format	Article
spelling	doaj-936d6ca0b0b747de8909fd63da7e87fc2021-01-27T00:06:44ZengMDPI AGGenes2073-44252021-01-011217017010.3390/genes12020170The Axenfeld–Rieger Syndrome Gene <i>FOXC1</i> Contributes to Left–Right PatterningPaul W. Chrystal0Curtis R. French1Francesca Jean2Serhiy Havrylov3Suey van Baarle4Ann-Marie Peturson5Pengfei Xu6J. Gage Crump7David B. Pilgrim8Ordan J. Lehmann9Andrew J. Waskiewicz10Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, CanadaDepartment of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, CanadaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USADepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USADepartment of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, CanadaDepartment of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, CanadaPrecise spatiotemporal expression of the <i>Nodal</i>-<i>Lefty</i>-<i>Pitx2</i> 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 <i>PITX2</i> and, separately, the Forkhead transcription factor <i>FOXC1</i> 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 <i>foxc1</i> contributes to organ laterality or situs. We demonstrate that CRISPR/Cas9-generated <i>foxc1a</i> and <i>foxc1b</i> mutants exhibit abnormal cardiac looping and that the prevalence of cardiac situs defects is increased in <i>foxc1a<sup>−/−</sup></i>; <i>foxc1b<sup>−/−</sup></i> 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 <i>foxc1a </i>and <i>foxc1b</i>. In addition, an analysis of the left–right patterning components, identified in the lateral plate mesoderm of <i>foxc1</i> mutants, reduced or abolished the expression of the <i>NODAL</i> antagonist <i>lefty2</i>. Together, these data reveal a novel contribution from <i>foxc1</i> to left–right patterning, demonstrating that this role is sensitive to <i>foxc1 </i>gene dosage, and provide a plausible mechanism for the incidence of congenital heart defects in Axenfeld–Rieger syndrome patients.https://www.mdpi.com/2073-4425/12/2/170<i>FOXC1</i>Axenfeld–Rieger syndromeleft–right patterningzebrafish<i>LEFTY</i>
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Paul W. Chrystal Curtis R. French Francesca Jean Serhiy Havrylov Suey van Baarle Ann-Marie Peturson Pengfei Xu J. Gage Crump David B. Pilgrim Ordan J. Lehmann Andrew J. Waskiewicz
spellingShingle	Paul W. Chrystal Curtis R. French Francesca Jean Serhiy Havrylov Suey van Baarle Ann-Marie Peturson Pengfei Xu J. Gage Crump David B. Pilgrim Ordan J. Lehmann Andrew J. Waskiewicz The Axenfeld–Rieger Syndrome Gene <i>FOXC1</i> Contributes to Left–Right Patterning Genes <i>FOXC1</i> Axenfeld–Rieger syndrome left–right patterning zebrafish <i>LEFTY</i>
author_facet	Paul W. Chrystal Curtis R. French Francesca Jean Serhiy Havrylov Suey van Baarle Ann-Marie Peturson Pengfei Xu J. Gage Crump David B. Pilgrim Ordan J. Lehmann Andrew J. Waskiewicz
author_sort	Paul W. Chrystal
title	The Axenfeld–Rieger Syndrome Gene <i>FOXC1</i> Contributes to Left–Right Patterning
title_short	The Axenfeld–Rieger Syndrome Gene <i>FOXC1</i> Contributes to Left–Right Patterning
title_full	The Axenfeld–Rieger Syndrome Gene <i>FOXC1</i> Contributes to Left–Right Patterning
title_fullStr	The Axenfeld–Rieger Syndrome Gene <i>FOXC1</i> Contributes to Left–Right Patterning
title_full_unstemmed	The Axenfeld–Rieger Syndrome Gene <i>FOXC1</i> Contributes to Left–Right Patterning
title_sort	axenfeld–rieger syndrome gene <i>foxc1</i> contributes to left–right patterning
publisher	MDPI AG
series	Genes
issn	2073-4425
publishDate	2021-01-01
description	Precise spatiotemporal expression of the <i>Nodal</i>-<i>Lefty</i>-<i>Pitx2</i> 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 <i>PITX2</i> and, separately, the Forkhead transcription factor <i>FOXC1</i> 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 <i>foxc1</i> contributes to organ laterality or situs. We demonstrate that CRISPR/Cas9-generated <i>foxc1a</i> and <i>foxc1b</i> mutants exhibit abnormal cardiac looping and that the prevalence of cardiac situs defects is increased in <i>foxc1a<sup>−/−</sup></i>; <i>foxc1b<sup>−/−</sup></i> 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 <i>foxc1a </i>and <i>foxc1b</i>. In addition, an analysis of the left–right patterning components, identified in the lateral plate mesoderm of <i>foxc1</i> mutants, reduced or abolished the expression of the <i>NODAL</i> antagonist <i>lefty2</i>. Together, these data reveal a novel contribution from <i>foxc1</i> to left–right patterning, demonstrating that this role is sensitive to <i>foxc1 </i>gene dosage, and provide a plausible mechanism for the incidence of congenital heart defects in Axenfeld–Rieger syndrome patients.
topic	<i>FOXC1</i> Axenfeld–Rieger syndrome left–right patterning zebrafish <i>LEFTY</i>
url	https://www.mdpi.com/2073-4425/12/2/170
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The Axenfeld–Rieger Syndrome Gene <i>FOXC1</i> Contributes to Left–Right Patterning

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