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Muñoz-Martín, N.* ; Simon-Chica, A.* ; Díaz-Díaz, C.* ; Cadenas, V.* ; Temiño, S.* ; Esteban, I.* ; Ludwig, A.* ; Schormair, B. ; Winkelmann, J. ; Olejnickova, V.* ; Sedmera, D.* ; Filgueiras-Rama, D.* ; Torres, M.*

Meis transcription factors regulate cardiac conduction system development and adult function.

Cardiovasc. Res., DOI: 10.1093/cvr/cvae258 (2024)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
AIMS: The Cardiac Conduction System (CCS) is progressively specified during development by interactions among a discrete number of Transcriptions Factors that ensure its proper patterning and the emergence of its functional properties. Meis genes encode homeodomain transcription factors (TFs) with multiple roles in mammalian development. In humans, Meis genes associate with congenital cardiac malformations and alterations of cardiac electrical activity, however the basis for these alterations has not been established. Here we studied the role of Meis transcription factors in cardiomyocyte development and function during mouse development and adult life. METHODS AND RESULTS: We studied Meis1 and Meis2 conditional deletion mouse models that allowed cardiomyocyte-specific elimination of Meis function during development and inducible elimination of Meis function in cardiomyocytes of the adult CCS. We studied cardiac anatomy, contractility and conduction. We report that Meis factors are global regulators of cardiac conduction, with a predominant role in the CCS. While constitutive Meis deletion in cardiomyocytes led to congenital malformations of the arterial pole and atria, as well as defects in ventricular conduction, Meis elimination in cardiomyocytes of the adult CCS produced sinus node dysfunction and delayed atrio-ventricular conduction. Molecular analyses unraveled Meis-controlled molecular pathways associated with these defects. Finally, we studied in transgenic mice the activity of a Meis1 human enhancer related to an SNP associated by GWAS to PR elongation and found that the transgene drives expression in components of the atrio-ventricular conduction system. CONCLUSIONS: Our study identifies Meis TFs as essential regulators of the establishment of cardiac conduction function during development and its maintenance during adult life. In addition, we generated animal models and identified molecular alterations that will ease the study of Meis-associated conduction defects and congenital malformations in humans.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cardiac development; PR elongation; Sinus node dysfunction; Transcription factor; Mouse targeted mutation; Hematopoietic Stem-cells; Genome-wide Association; Ventricular Septum; Frizzled 2; Gene; Mice; Defects; Palate; Pbx; Closure
ISSN (print) / ISBN 0008-6363
e-ISSN 1755-3245
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Non-patent literature Publications
Reviewing status Peer reviewed
Grants
Spanish Ministerio de Ciencia e Innovacion
Comunidad de Madrid
Ministry of Education, Youth and Sports of the Czech Republic
Czech Science Foundation
The 'la Caixa' Foundation Severo Ochoa PhD Fellowship
Ministerio de Ciencia e Innovacion
Pro CNIC Foundation and is a Severo Ochoa Center of Excellence - MICIU/AEI
H2020 Societal Changes Program