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Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development

Congenital heart disease is one of the leading causes of pediatric morbidity and mortality, thus highlighting the importance of deciphering the molecular mechanisms that control heart development. As the terminal transcriptional effectors of the Hippo–YAP pathway, YAP and TEAD1 form a transcriptiona...

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Autores principales: Sheldon, Caroline, Farley, Aaron, Ma, Qing, Pu, William T., Lin, Zhiqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496954/
https://www.ncbi.nlm.nih.gov/pubmed/36139407
http://dx.doi.org/10.3390/cells11182832
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author Sheldon, Caroline
Farley, Aaron
Ma, Qing
Pu, William T.
Lin, Zhiqiang
author_facet Sheldon, Caroline
Farley, Aaron
Ma, Qing
Pu, William T.
Lin, Zhiqiang
author_sort Sheldon, Caroline
collection PubMed
description Congenital heart disease is one of the leading causes of pediatric morbidity and mortality, thus highlighting the importance of deciphering the molecular mechanisms that control heart development. As the terminal transcriptional effectors of the Hippo–YAP pathway, YAP and TEAD1 form a transcriptional complex that regulates the target gene expression and depletes either of these two genes in cardiomyocytes, thus resulting in cardiac hypoplasia. Vestigial-like 4 (VGLL4) is a transcriptional co-factor that interacts with TEAD and suppresses the YAP/TEAD complex by competing against YAP for TEAD binding. To understand the VGLL4 function in the heart, we generated two VGLL4 loss-of-function mouse lines: a germline Vgll4 depletion allele and a cardiomyocyte-specific Vgll4 depletion allele. The whole-body deletion of Vgll4 caused defective embryo development and perinatal lethality. The analysis of the embryos at day 16.5 revealed that Vgll4 knockout embryos had reduced body size, malformed tricuspid valves, and normal myocardium. Few whole-body Vgll4 knockout pups could survive up to 10 days, and none of them showed body weight gain. In contrast to the whole-body Vgll4 knockout mutants, cardiomyocyte-specific Vgll4 knockout mice had no noticeable heart growth defects and had normal heart function. In summary, our data suggest that VGLL4 is required for embryo development but dispensable for myocardial growth.
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spelling pubmed-94969542022-09-23 Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development Sheldon, Caroline Farley, Aaron Ma, Qing Pu, William T. Lin, Zhiqiang Cells Article Congenital heart disease is one of the leading causes of pediatric morbidity and mortality, thus highlighting the importance of deciphering the molecular mechanisms that control heart development. As the terminal transcriptional effectors of the Hippo–YAP pathway, YAP and TEAD1 form a transcriptional complex that regulates the target gene expression and depletes either of these two genes in cardiomyocytes, thus resulting in cardiac hypoplasia. Vestigial-like 4 (VGLL4) is a transcriptional co-factor that interacts with TEAD and suppresses the YAP/TEAD complex by competing against YAP for TEAD binding. To understand the VGLL4 function in the heart, we generated two VGLL4 loss-of-function mouse lines: a germline Vgll4 depletion allele and a cardiomyocyte-specific Vgll4 depletion allele. The whole-body deletion of Vgll4 caused defective embryo development and perinatal lethality. The analysis of the embryos at day 16.5 revealed that Vgll4 knockout embryos had reduced body size, malformed tricuspid valves, and normal myocardium. Few whole-body Vgll4 knockout pups could survive up to 10 days, and none of them showed body weight gain. In contrast to the whole-body Vgll4 knockout mutants, cardiomyocyte-specific Vgll4 knockout mice had no noticeable heart growth defects and had normal heart function. In summary, our data suggest that VGLL4 is required for embryo development but dispensable for myocardial growth. MDPI 2022-09-10 /pmc/articles/PMC9496954/ /pubmed/36139407 http://dx.doi.org/10.3390/cells11182832 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sheldon, Caroline
Farley, Aaron
Ma, Qing
Pu, William T.
Lin, Zhiqiang
Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development
title Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development
title_full Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development
title_fullStr Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development
title_full_unstemmed Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development
title_short Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development
title_sort depletion of vgll4 causes perinatal lethality without affecting myocardial development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496954/
https://www.ncbi.nlm.nih.gov/pubmed/36139407
http://dx.doi.org/10.3390/cells11182832
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