Meis transcription factors regulate cardiac conduction system development and adult function

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Molecular Genetics

Background:

• The cardiac conduction system (CCS) requires precise development regulated by transcription factors (TFs).
• Meis genes encode homeodomain TFs implicated in human congenital heart malformations and electrical activity alterations.
• The specific role of Meis TFs in cardiomyocyte development and cardiac electrical function remains unclear.

Purpose of the Study:

• To investigate the function of Meis TFs in cardiomyocyte development and function during mouse embryogenesis and in adult life.
• To elucidate the molecular mechanisms underlying Meis TF-associated cardiac conduction defects.

Main Methods:

• Generation of Meis1 and Meis2 conditional deletion mouse models for cardiomyocyte-specific gene elimination during development and in adulthood.
• Assessment of cardiac anatomy, contractility, and electrophysiology.
• Molecular analyses to identify Meis-controlled pathways.
• Study of a human Meis1 enhancer in transgenic mice.

Main Results:

• Meis factors are global regulators of cardiac conduction, with a key role in the CCS.
• Constitutive Meis deletion caused congenital defects in the arterial pole, atria, and ventricular conduction.
• Adult Meis elimination in the CCS led to sinus node dysfunction and atrio-ventricular conduction delay.
• Molecular pathways regulated by Meis TFs were identified.
• A human Meis1 enhancer associated with PR elongation showed expression in the atrio-ventricular conduction system.

Conclusions:

• Meis TFs are essential for establishing and maintaining cardiac conduction function throughout life.
• The study provides animal models and molecular insights for investigating Meis-associated congenital heart malformations and conduction defects.