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Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish

Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for...

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Autores principales: Bartman, Thomas, Walsh, Emily C, Wen, Kuo-Kuang, McKane, Melissa, Ren, Jihui, Alexander, Jonathan, Rubenstein, Peter A, Stainier, Didier Y. R
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2004
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC406391/
https://www.ncbi.nlm.nih.gov/pubmed/15138499
http://dx.doi.org/10.1371/journal.pbio.0020129
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author Bartman, Thomas
Walsh, Emily C
Wen, Kuo-Kuang
McKane, Melissa
Ren, Jihui
Alexander, Jonathan
Rubenstein, Peter A
Stainier, Didier Y. R
author_facet Bartman, Thomas
Walsh, Emily C
Wen, Kuo-Kuang
McKane, Melissa
Ren, Jihui
Alexander, Jonathan
Rubenstein, Peter A
Stainier, Didier Y. R
author_sort Bartman, Thomas
collection PubMed
description Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih(−/−)) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk(−/−)) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk(−/−) embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfk(s11) variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease.
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spelling pubmed-4063912004-05-11 Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish Bartman, Thomas Walsh, Emily C Wen, Kuo-Kuang McKane, Melissa Ren, Jihui Alexander, Jonathan Rubenstein, Peter A Stainier, Didier Y. R PLoS Biol Research Article Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih(−/−)) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk(−/−)) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk(−/−) embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfk(s11) variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease. Public Library of Science 2004-05 2004-05-11 /pmc/articles/PMC406391/ /pubmed/15138499 http://dx.doi.org/10.1371/journal.pbio.0020129 Text en Copyright: ©2004 Bartman et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bartman, Thomas
Walsh, Emily C
Wen, Kuo-Kuang
McKane, Melissa
Ren, Jihui
Alexander, Jonathan
Rubenstein, Peter A
Stainier, Didier Y. R
Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish
title Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish
title_full Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish
title_fullStr Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish
title_full_unstemmed Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish
title_short Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish
title_sort early myocardial function affects endocardial cushion development in zebrafish
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC406391/
https://www.ncbi.nlm.nih.gov/pubmed/15138499
http://dx.doi.org/10.1371/journal.pbio.0020129
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