Pitx2 confers left morphological, molecular, and functional identity to the sinus venosus myocardium

AIMS: The sinus venous myocardium, comprising the sinoatrial node (SAN) and sinus horns (SH), is a region subject to congenital malformations and cardiac arrhythmias. It differentiates from symmetric bilateral mesenchymal precursors, but morphological, molecular, and functional left/right differences are progressively established through development. The role of the laterality gene Pitx2 in this process is unknown. We aimed to elucidate the molecular events driving left/right patterning in the sinus venosus (SV) myocardium by using a myocardial Pitx2 knockout mouse. METHODS AND RESULTS: We generated a myocardial specific Pitx2 knockout model (cTP mice). cTP embryos present several features of Pitx2 null, including right atrial isomerism with bilateral SANs and symmetric atrial entrance of the systemic veins. By in situ hybridization and optical mapping analysis, we compared throughout development the molecular and functional properties of the SV myocardium in wt and mutant embryos. We observed that Pitx2 prevents the expansion of the left-SAN primordium at the onset of its differentiation into myocardium; Pitx2 promotes expansion of the left SH through development; Pitx2 dose-dependently represses the autorhythmic properties of the left SV myocardium at mid-gestation (E14.5); Pitx2 modulates late foetal gene expression at the left SH-derived superior caval vein. CONCLUSION: Pitx2 drives left/right patterning of the SV myocardium through multiple developmental steps. Overall, Pitx2 plays a crucial functional role by negatively modulating a nodal-type programme in the left SV myocardium

Outflow tract septation and the aortic arch system in reptiles: lessons for understanding the mammalian heart

Animal science

Development of the sinus venosus myocardium from the posterior second heart field : implications for sinoatrial and atrioventricular mode development

While the embryonic heart is developing and maturing towards its four-chambered form, the cardiac conduction system (CCS) is developing as well. The CCS will provide the heart with the required wiring system to ensure the properly orchestrated contraction of the myocardial chambers. In both the young and adult population rhythm disturbances or cardiac arrhythmias can occur. Electrophysiological studies have shown that these events do not occur randomly in the heart but rather at anatomical predilection sites. This thesis presents our results on the morphological as well as electrophysiological changes that occur during heart development, specifically in the developing sinoatrial and atrioventricular node. By studying the developmental changes we aim to increase our knowledge on the mechanism underlying arrhythmias.Netherlands Heart Foundation Boston Scientific B.V. Sorin Group Nederland N.V. Toshiba Medical Systems Netherlands Biotronik B.V. Bayer B.V.UBL - phd migration 201

Does the Dorsal Mesenchymal Protrusion Act as a Temporary Pacemaker during Heart Development?

Cardiolog

Remodelling of the atrioventricular canal myocardium determines atrioventricular conduction patterns

Developmen

Remodelling of the atrioventricular canal myocardium determines atrioventricular conduction patterns

Developmen

The avian embryo to study development of the cardiac conduction system

Cardiolog

Does the Dorsal Mesenchymal Protrusion Act as a Temporary Pacemaker during Heart Development?

Cardiolog