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The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development

During heart development, epicardial cells residing within the outer layer undergo epithelial-mesenchymal transition (EMT) and migrate into the underlying myocardium to support organ growth and morphogenesis. Disruption of epicardial EMT results in embryonic lethality, yet its regulation is poorly u...

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Autores principales: Sun, Xin, Malandraki-Miller, Sophia, Kennedy, Tahnee, Bassat, Elad, Klaourakis, Konstantinos, Zhao, Jia, Gamen, Elisabetta, Vieira, Joaquim Miguel, Tzahor, Eldad, Riley, Paul R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172119/
https://www.ncbi.nlm.nih.gov/pubmed/33969874
http://dx.doi.org/10.1242/dev.197525
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author Sun, Xin
Malandraki-Miller, Sophia
Kennedy, Tahnee
Bassat, Elad
Klaourakis, Konstantinos
Zhao, Jia
Gamen, Elisabetta
Vieira, Joaquim Miguel
Tzahor, Eldad
Riley, Paul R.
author_facet Sun, Xin
Malandraki-Miller, Sophia
Kennedy, Tahnee
Bassat, Elad
Klaourakis, Konstantinos
Zhao, Jia
Gamen, Elisabetta
Vieira, Joaquim Miguel
Tzahor, Eldad
Riley, Paul R.
author_sort Sun, Xin
collection PubMed
description During heart development, epicardial cells residing within the outer layer undergo epithelial-mesenchymal transition (EMT) and migrate into the underlying myocardium to support organ growth and morphogenesis. Disruption of epicardial EMT results in embryonic lethality, yet its regulation is poorly understood. Here, we report epicardial EMT within the mesothelial layer of the mouse embryonic heart at ultra-high resolution using scanning electron microscopy combined with immunofluorescence analyses. We identified morphologically active EMT regions that associated with key components of the extracellular matrix, including the basement membrane-associated proteoglycan agrin. Deletion of agrin resulted in impaired EMT and compromised development of the epicardium, accompanied by downregulation of Wilms’ tumor 1. Agrin enhanced EMT in human embryonic stem cell-derived epicardial-like cells by decreasing β-catenin and promoting pFAK localization at focal adhesions, and promoted the aggregation of dystroglycan within the Golgi apparatus in murine epicardial cells. Loss of agrin resulted in dispersal of dystroglycan in vivo, disrupting basement membrane integrity and impairing EMT. Our results provide new insights into the role of the extracellular matrix in heart development and implicate agrin as a crucial regulator of epicardial EMT.
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spelling pubmed-81721192021-06-08 The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development Sun, Xin Malandraki-Miller, Sophia Kennedy, Tahnee Bassat, Elad Klaourakis, Konstantinos Zhao, Jia Gamen, Elisabetta Vieira, Joaquim Miguel Tzahor, Eldad Riley, Paul R. Development Research Article During heart development, epicardial cells residing within the outer layer undergo epithelial-mesenchymal transition (EMT) and migrate into the underlying myocardium to support organ growth and morphogenesis. Disruption of epicardial EMT results in embryonic lethality, yet its regulation is poorly understood. Here, we report epicardial EMT within the mesothelial layer of the mouse embryonic heart at ultra-high resolution using scanning electron microscopy combined with immunofluorescence analyses. We identified morphologically active EMT regions that associated with key components of the extracellular matrix, including the basement membrane-associated proteoglycan agrin. Deletion of agrin resulted in impaired EMT and compromised development of the epicardium, accompanied by downregulation of Wilms’ tumor 1. Agrin enhanced EMT in human embryonic stem cell-derived epicardial-like cells by decreasing β-catenin and promoting pFAK localization at focal adhesions, and promoted the aggregation of dystroglycan within the Golgi apparatus in murine epicardial cells. Loss of agrin resulted in dispersal of dystroglycan in vivo, disrupting basement membrane integrity and impairing EMT. Our results provide new insights into the role of the extracellular matrix in heart development and implicate agrin as a crucial regulator of epicardial EMT. The Company of Biologists Ltd 2021-05-10 /pmc/articles/PMC8172119/ /pubmed/33969874 http://dx.doi.org/10.1242/dev.197525 Text en © 2021. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Sun, Xin
Malandraki-Miller, Sophia
Kennedy, Tahnee
Bassat, Elad
Klaourakis, Konstantinos
Zhao, Jia
Gamen, Elisabetta
Vieira, Joaquim Miguel
Tzahor, Eldad
Riley, Paul R.
The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development
title The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development
title_full The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development
title_fullStr The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development
title_full_unstemmed The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development
title_short The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development
title_sort extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172119/
https://www.ncbi.nlm.nih.gov/pubmed/33969874
http://dx.doi.org/10.1242/dev.197525
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