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Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network

The ventricular conduction system coordinates heartbeats by rapid propagation of electrical activity through the Purkinje fiber (PF) network. PFs share common progenitors with contractile cardiomyocytes, yet the mechanisms of segregation and network morphogenesis are poorly understood. Here, we appl...

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Detalles Bibliográficos
Autores principales: Choquet, Caroline, Kelly, Robert G., Miquerol, Lucile
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575572/
https://www.ncbi.nlm.nih.gov/pubmed/33082351
http://dx.doi.org/10.1038/s41467-020-19150-9
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author Choquet, Caroline
Kelly, Robert G.
Miquerol, Lucile
author_facet Choquet, Caroline
Kelly, Robert G.
Miquerol, Lucile
author_sort Choquet, Caroline
collection PubMed
description The ventricular conduction system coordinates heartbeats by rapid propagation of electrical activity through the Purkinje fiber (PF) network. PFs share common progenitors with contractile cardiomyocytes, yet the mechanisms of segregation and network morphogenesis are poorly understood. Here, we apply genetic fate mapping and temporal clonal analysis to identify murine cardiomyocytes committed to the PF lineage as early as E7.5. We find that a polyclonal PF network emerges by progressive recruitment of conductive precursors to this scaffold from a pool of bipotent progenitors. At late fetal stages, the segregation of conductive cells increases during a phase of rapid recruitment to build the definitive PF network through a non-cell autonomous mechanism. We also show that PF differentiation is impaired in Nkx2-5 haploinsufficient embryos leading to failure to extend the scaffold. In particular, late fetal recruitment fails, resulting in PF hypoplasia and persistence of bipotent progenitors. Our results identify how transcription factor dosage regulates cell fate divergence during distinct phases of PF network morphogenesis.
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spelling pubmed-75755722020-10-29 Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network Choquet, Caroline Kelly, Robert G. Miquerol, Lucile Nat Commun Article The ventricular conduction system coordinates heartbeats by rapid propagation of electrical activity through the Purkinje fiber (PF) network. PFs share common progenitors with contractile cardiomyocytes, yet the mechanisms of segregation and network morphogenesis are poorly understood. Here, we apply genetic fate mapping and temporal clonal analysis to identify murine cardiomyocytes committed to the PF lineage as early as E7.5. We find that a polyclonal PF network emerges by progressive recruitment of conductive precursors to this scaffold from a pool of bipotent progenitors. At late fetal stages, the segregation of conductive cells increases during a phase of rapid recruitment to build the definitive PF network through a non-cell autonomous mechanism. We also show that PF differentiation is impaired in Nkx2-5 haploinsufficient embryos leading to failure to extend the scaffold. In particular, late fetal recruitment fails, resulting in PF hypoplasia and persistence of bipotent progenitors. Our results identify how transcription factor dosage regulates cell fate divergence during distinct phases of PF network morphogenesis. Nature Publishing Group UK 2020-10-20 /pmc/articles/PMC7575572/ /pubmed/33082351 http://dx.doi.org/10.1038/s41467-020-19150-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Choquet, Caroline
Kelly, Robert G.
Miquerol, Lucile
Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network
title Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network
title_full Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network
title_fullStr Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network
title_full_unstemmed Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network
title_short Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network
title_sort nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac purkinje fiber network
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575572/
https://www.ncbi.nlm.nih.gov/pubmed/33082351
http://dx.doi.org/10.1038/s41467-020-19150-9
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