Morphogenesis, that is the acquisition of a shape, is essential for organ function. The heart is an asymmetric organ, in which the left and right sides are specified for the establishment of a double blood circulation in mammals. Whereas the molecular cascade initiating left-right patterning has been well characterised in the early embryo, how it is later sensed by organ specific precursor cells to generate asymmetric morphogenesis is currently unknown. Our aim is to dissect how patterning of heart precursors drives asymmetric heart morphogenesis, and how anomalies in this process are associated with congenital heart defects.
In the early embryo, looping of the heart tube, is the first morphological sign of left-right asymmetry. It corresponds to the transformation of the initial straight heart tube into a helix. Heart looping is essential to align the cardiac chambers and great vessels and thus establish the plumbing of the blood flow. Previously, heart looping was described solely for its direction (rightward, leftward, indeterminate ). Using High Resolution Episcopic Microscopy (HREM), we have now reconstructed mouse heart looping dynamics in 3 dimensions and developed tools to quantify the shape of the heart tube, not just its direction.
We have proposed a novel mechanism of heart looping and developed a computer model, to predict the shape of the looped heart tube from initial mechanical constraints and left-right asymmetries.
Le Garrec et al., 2017 – Video of a computer simulation of heart looping
In a recent review, we have compared heart looping mechanisms and dynamics in the main vertebrate models : the fish, chick and mouse.
Our work on mouse heart morphogenesis is relevant to congenital heart defects in humans, such as misalignment of cardiac chambers. Congenital heart diseases represent a major concern for public health, affecting 8‰ newborns and leading to 30% of embryonic deaths in utero. However, the genetic bases of these defects and the underlying pathophysiological processes remain poorly understood.
Phenotyping of laterality defects, such as heterotaxy, has been limited by fragmented observations. We have now established a standardised procedure for a multiscale, multistage, 3D analysis of visceral organ asymmetry in their normal environment, together with that of the fine anatomy of left/right cardiac segments.