AIMS: The cardiac conduction system (CCS) is progressively specified during development by interactions among a discrete number of transcription factors (TFs) that ensure its proper patterning and the emergence of its functional properties. Meis genes encode homeodomain 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 TFs 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 unravelled Meis-controlled molecular pathways associated with these defects. Finally, we studied in transgenic mice the activity of a Meis1 human enhancer related to an single-nucleotide polymorphism (SNP) associated by Genome-wide association studies (GWAS) to PR (P and R waves of the electrocardiogram) elongation and found that the transgene drives expression in components of the atrio-ventricular conduction system. CONCLUSION: 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.
- MeSH
- akční potenciály MeSH
- fenotyp MeSH
- homeodoménové proteiny * genetika metabolismus MeSH
- kardiomyocyty * metabolismus patologie MeSH
- kontrakce myokardu MeSH
- myši knockoutované MeSH
- nodus sinuatrialis metabolismus patofyziologie MeSH
- převodní systém srdeční * metabolismus patofyziologie růst a vývoj MeSH
- srdeční arytmie patofyziologie metabolismus genetika MeSH
- srdeční frekvence * MeSH
- transkripční faktor Meis1 * genetika metabolismus nedostatek MeSH
- věkové faktory MeSH
- vrozené srdeční vady metabolismus genetika patofyziologie MeSH
- vývojová regulace genové exprese MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- chemická stimulace MeSH
- elektrická stimulace MeSH
- krysa rodu rattus MeSH
- nervová zakončení metabolismus MeSH
- noradrenalin MeSH
- převodní systém srdeční inervace růst a vývoj MeSH
- srdce - funkce síní MeSH
- srdeční síně MeSH
- sympatický nervový systém fyziologie MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
