Left-right asymmetry of the heart : forming the right loop
Presented by: Sigolene Meilhac
Presentation time:
Left-right partitioning of the heart underlies the double blood circulation. Impairment of left-right patterning leads to heterotaxy, including complex cardiac malformations. Asymmetric heart morphogenesis is initiated in the embryo, when the initial tubular primordium acquires a rightward helical shape during the process of heart looping. This shape change determines cardiac chamber alignment. Whereas the molecular cascade breaking the symmetry has been well characterised, how asymmetric signalling is sensed by precursor cells to generate asymmetric organogenesis has remained largely unknown.
Heart looping has been previously analysed as a readout of the symmetry-breaking event, with a binary parameter, the helix direction. However, this is too reductionist to describe a 3D shape. We have developed a novel framework to quantify and simulate the fine heart loop shape in the mouse, as a readout of asymmetric morphogenesis. This has led us to propose a model of heart looping, centred on the buckling of the tube growing between fixed poles. We have now re-analysed the role of the major left determinant Nodal. Nodal expressing cells contribute to the arterial and venous poles. By manipulating Nodal signalling in time and space, we show that it is not involved in the buckling, but that it is required transiently in heart precursors, to amplify and coordinate opposed asymmetries at the heart tube poles. Thus, Nodal is not required to initiate asymmetry, but rather to bias it and generate a robust helical heart loop shape. By RNA sequencing, we identified downstream effectors of Nodal signalling at the heart poles, regulating cell proliferation, cell differentiation and the extra-cellular matrix composition.
Our work shows that left-right patterning is not a single event, occurring in the node, but rather a dynamic process, which is relevant to the variable phenotypes of heterotaxy.
Heart looping has been previously analysed as a readout of the symmetry-breaking event, with a binary parameter, the helix direction. However, this is too reductionist to describe a 3D shape. We have developed a novel framework to quantify and simulate the fine heart loop shape in the mouse, as a readout of asymmetric morphogenesis. This has led us to propose a model of heart looping, centred on the buckling of the tube growing between fixed poles. We have now re-analysed the role of the major left determinant Nodal. Nodal expressing cells contribute to the arterial and venous poles. By manipulating Nodal signalling in time and space, we show that it is not involved in the buckling, but that it is required transiently in heart precursors, to amplify and coordinate opposed asymmetries at the heart tube poles. Thus, Nodal is not required to initiate asymmetry, but rather to bias it and generate a robust helical heart loop shape. By RNA sequencing, we identified downstream effectors of Nodal signalling at the heart poles, regulating cell proliferation, cell differentiation and the extra-cellular matrix composition.
Our work shows that left-right patterning is not a single event, occurring in the node, but rather a dynamic process, which is relevant to the variable phenotypes of heterotaxy.