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ABSTRACT: Developmental genetics of congenital heart diseases have evolved from analysis of embryonic hearts towards molecular genetics of cardiac morphogenesis with a dynamic view of cardiac development. Ablation techniques, transgenic animal models and clonal analysis of the developing heart led to identification of different cardiac lineages and their respective roles. The mechanistic approach for great arteries anomalies has led to emerging concepts such as common embryological origin of anatomically different cardiac defects, phenotypic continuum of left heart obstructive defects, or developmental algorithms for cardiac isomerisms. Recent experiments that demonstrated the myocardial rotation of the outflow tract in mouse embryos led to a better understanding of the origin of transposition of the large arteries. This has also raised the hypothesis of a new group of congenital heart anomalies defined as laterality defects limited to a segment of the embryonic heart. These results confirm that genetic heterogeneity of congenital heart defects is related to the heterogeneity of the mechanisms that finally produce the same phenotype.
Journal de la Société de Biologie 02/2009; 203(2):161-5.
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ABSTRACT: In order to follow cardiac precursor cells, we have adopted a retrospective clonal approach, based on the nlaacZ genetic label. Random clones were generated and observed at different developmental stages in murine myocardium. The distribution of these clones in clusters suggest for the first time that cells fated to form myocardium proliferate in two steps. The first growth phase, before E8.5, is dispersive and polarised along the axis of the primitive cardiac tube, contributing to its elongation. The second growth phase is coherent and polarised differentially in different cardiac subregions. Interestingly, this can be correlated with production of geometrical forms (dilatation of a sphere, enlargement of a tube), showing the relation between heart morphogenesis and the controlled proliferation of myocardial cells. The restricted distribution of clones to the right or left ventricule was also investigated with the goal of establishing the time at which cardiac chamber identity emerges. Right and left ventricular lineages appear to segregate early, in agreement with the existence of two populations of cardiac precursors, the so-called primary (or posterior) and secondary (or anterior) heart fields.
Journal de la Société de Biologie 02/2003; 197(2):179-86.
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ABSTRACT: The heart is one of the first organs to form during embryogenesis since its circulatory function is critical from early stages for embryo survival. In man, morphological events are affected by molecular perturbations, which can lead to a congenital heart defect. It is important therefore to understand not only the molecular signals, but also the morphological events, which govern myocardial cell identity. The study of transgenic mouse lines, Mlc1v-nlacZ-24 and Mlc3f-nlacZ-2, has led to the identification of a new precardiac territory, the anterior heart field, which has also been described recently in birds, and which contributes to the myocardium of the arterial pole of the heart. The use of explant cultures also indicates that pharyngeal mesoderm participates in the formation of the outflow tract and right ventricle and shows that the primitive heart tube has a predominantly left ventricular identity. We have also shown that Fgf-10 is expressed in the anterior heart field, where a role for FGF signaling in arterial pole morphogenesis is suggested by inhibitor experiments. Finally explant cultures have been employed to examine the acquisition of left-right atrial identity. The Mlc3f-nlacZ-2 line, which marks the right atrium, allowed us to determine the time window during which left-right signaling confers left-right atrial identity.
Journal de la Société de Biologie 02/2003; 197(2):187-94.
