Early asymmetry required for the alignment of cardiac chambers : development and pathology – Heart_asymmetry

During embryo development, looping of the heart tube is the first morphological sign of left-right asymmetry. It is required for the alignment of cardiac chambers and thus the plumbing of the blood flow. Whereas the molecular cascade initiating left-right patterning has been well characterised in the early embryo, how it is later transposed in different populations of cardiac precursor cells for heart looping remains poorly understood. Our aim is to understand how left-right signalling controls the mechanism of heart looping and the alignment of cardiac chambers using cutting-edge technologies. Our preliminary results by computer modelling, mouse genetics and human genetics have validated the feasibility of the project. In the mouse model, we will dissect the role of the left determinant Nodal by conditional gene inactivation. The mechanism of heart looping, as well as the structural defects in chamber alignment that might fit with human heart diseases, will be analysed using High Resolution Episcopic Microscopy (HREM). To identify novel markers of the left and right heart fields, we will adopt a genome-wide transcriptional approach, tomo-seq. On a clinical point of view, we will focus on a rare cardiac malformation, Congenitally Corrected Transposition of the Great Arteries (CCTGA), a model of abnormal heart looping characterized by the left/right inversion of the ventricles. Taking advantage of a large cohort of patients and the associated collection of DNA samples (CARREG) and phenotypic descriptions, we aim to analyse the functional characteristics of CCTGA by multimodal imaging, as well as the genetic variations by whole genome sequencing. Selected genetic variations will be validated in the zebrafish model and also by developing novel mouse models. This will open perspectives to study the pathological mechanisms involved, with particular reference to heart looping. Combining pediatric cardiology, human genetics and developmental biology to analyse the left-right asymmetry of the heart, our innovative project is expected to impact both fundamental research for the mechanism of left-right patterning during organogenesis, as well as clinical practice for genetic counselling and prognosis of cardiac chamber misalignment, representing about 20% of congenital heart defects (CHD), the most common malformation in humans.