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

0390178 - FGÚ 2013 RIV NL eng J - Journal Article
Ammirabile, G. - Tessari, A. - Pignataro, V. - Szumska, D. - Sardo, F.S. - Beneš Jr., Jiří - Balistreri, M. - Bhattacharya, S. - Sedmera, David - Campione, M.
Pitx2 confers left morphological, molecular, and functional identity to the sinus venosus myocardium.
Cardiovascular Research. Roč. 93, č. 2 (2012), s. 291-301. ISSN 0008-6363. E-ISSN 1755-3245
R&D Projects: GA ČR(CZ) GA304/08/0615
Institutional research plan: CEZ:AV0Z50110509
Keywords : Pitx2 * sinus venosus myocardium * optical mapping * mouse cardiac development
Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery
Impact factor: 5.940, year: 2012

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. 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. 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
Permanent Link: http://hdl.handle.net/11104/0219106