dc.contributor.author | Grego-Bessa, Joaquim | |
dc.contributor.author | Gomez-Apinaniz, Paula | |
dc.contributor.author | Prados, Belen | |
dc.contributor.author | Gómez, Manuel José | |
dc.contributor.author | MacGrogan, Donal | |
dc.contributor.author | de la Pompa, Jose Luis | |
dc.date.accessioned | 2024-02-19T15:08:39Z | |
dc.date.available | 2024-02-19T15:08:39Z | |
dc.date.issued | 2023-11-10 | |
dc.identifier.citation | Circ Res. 2023 Nov 10;133(11):927-943. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/18222 | |
dc.description.abstract | BACKGROUND
Cardiac ventricles provide the contractile force of the beating heart throughout life. How the primitive endocardium-layered myocardial projections called trabeculae form and mature into the adult ventricles is of great interest for biology and regenerative medicine. Trabeculation is dependent on the signaling protein Nrg1 (neuregulin-1). However, the mechanism of action of Nrg1 and its role in ventricular wall maturation are poorly understood.
METHODS
We investigated the functions and downstream mechanisms of Nrg1 signaling during ventricular chamber development using confocal imaging, transcriptomics, and biochemical approaches in mice with cardiac-specific inactivation or overexpression of Nrg1.
RESULTS
Analysis of cardiac-specific Nrg1 mutant mice showed that the transcriptional program underlying cardiomyocyte-oriented cell division and trabeculae formation depends on endocardial Nrg1 to myocardial ErbB2 (erb-b2 receptor tyrosine kinase 2) signaling and phospho-Erk (phosphorylated extracellular signal-regulated kinase; pErk) activation. Early endothelial loss of Nrg1 and reduced pErk activation diminished cardiomyocyte Pard3 and Crumbs2 (Crumbs Cell Polarity Complex Component 2) protein and altered cytoskeletal gene expression and organization. These alterations are associated with abnormal gene expression related to mitotic spindle organization and a shift in cardiomyocyte division orientation. Nrg1 is crucial for trabecular growth and ventricular wall thickening by regulating an epithelial-to-mesenchymal transition-like process in cardiomyocytes involving migration, adhesion, cytoskeletal actin turnover, and timely progression through the cell cycle G2/M phase. Ectopic cardiac Nrg1 overexpression and high pErk signaling caused S-phase arrest, sustained high epithelial-to-mesenchymal transition-like gene expression, and prolonged trabeculation, blocking compact myocardium maturation. Myocardial trabecular patterning alterations resulting from above- or below-normal Nrg1-dependent pErk activation were concomitant with sarcomere actin cytoskeleton disorganization. The Nrg1 loss- and gain-of-function transcriptomes were enriched for Yap1 (yes-associated protein-1) gene signatures, identifying Yap1 as a potential downstream effector. Furthermore, biochemical and imaging data reveal that Nrg1 influences pErk activation and Yap1 nuclear-cytoplasmic distribution during trabeculation.
CONCLUSIONS
These data establish the Nrg1-ErbB2/ErbB4-Erk axis as a crucial regulator of cardiomyocyte cell cycle progression and migration during ventricular development. | es_ES |
dc.description.sponsorship | This study was supported by grants PID2019-104776RB-I00 and PID2020-
120326RB-I00, CB16/11/00399 (Centro de investigación Biomédica en Red
Cardiovascular [CIBER CV]) from Ministerio de Ciencia e Innovación (MCIN)/
Agencia Española de Investigación (AEI)/10.13039/501100011033, Fundación Banco Bilbao Vizcaya Argentaria (BBVA; reference number: BIO14_298),
Fundació La Marató de TV3 (reference number: 20153431), and the Spanish
Society for Cardiology (SECSCFG-INV-CFG 21/004) to J.L. de la Pompa. J.
Grego-Bessa was funded by Programa Atracción de Talento from Comunidad de
Madrid (reference number 2016T1/BMD1540). Support for this publication also
came from the European Regional Development Fund. The Centro Nacional de
Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the Instituto
de Salud Carlos III (ISCIII), MCIN, and the Pro-CNIC Foundation and is a Severo
Ochoa Center of Excellence (grant CEX2020001041-S) financed by MCIN/
AEI/10.13039/501100011033. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Lippincott Williams & Wilkins (LWW) | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject.mesh | Myocytes, Cardiac | es_ES |
dc.subject.mesh | Neuregulin-1 | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | Myocardium | es_ES |
dc.subject.mesh | Heart Ventricles | es_ES |
dc.subject.mesh | Cell Division | es_ES |
dc.title | Nrg1 Regulates Cardiomyocyte Migration and Cell Cycle in Ventricular Development. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.identifier.pubmedID | 37846569 | es_ES |
dc.format.volume | 133 | es_ES |
dc.format.number | 11 | es_ES |
dc.format.page | 927 | es_ES |
dc.identifier.doi | 10.1161/CIRCRESAHA.123.323321 | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | Fundación BBVA | es_ES |
dc.contributor.funder | Fundación La Marató TV3 | es_ES |
dc.contributor.funder | Sociedad Española de Cardiología | es_ES |
dc.contributor.funder | Comunidad de Madrid (España) | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1524-4571 | es_ES |
dc.relation.publisherversion | 10.1161/CIRCRESAHA.123.323321 | es_ES |
dc.identifier.journal | Circulation research | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Señalización Intercelular durante el Desarrollo y la Enfermedad Cardiovascular | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2019-104776RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2020-120326RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/CB16/11/00399 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BIO14_298 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/20153431 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/SECSCFG-INV-CFG 21/004 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/2016T1/BMD1540 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/MCIN/AEI/10.13039/501100011033/CEX2020001041-S | es_ES |