Identification of Greb1l as a genetic determinant of crisscross heart in mice showing torsion of the heart tube by shortage of progenitor cells

Despite their burden, most congenital defects remain poorly understood, due to lack of knowledge of embryological mechanisms. Here, we identify Greb1l mutants as a mouse model of crisscross heart. Based on 3D quantifications of shape changes, we demonstrate that torsion of the atrioventricular canal occurs together with supero-inferior ventricles at E10.5, after heart looping. Mutants phenocopy partial deficiency in retinoic acid signaling, which reflect overlapping pathways in cardiac precursors. Spatiotemporal gene mapping and cross-correlated transcriptomic analyses further reveal the role of Greb1l in maintaining a pool of dorsal pericardial wall precursor cells during heart tube elongation, likely by controlling ribosome biogenesis and cell differentiation. Consequently, we observe growth arrest and malposition of the outflow tract, which are predictive of abnormal tube remodeling in mutants. Our work on a rare cardiac malformation opens novel perspectives on the origin of a broader spectrum of congenital defects associated with GREB1L in humans.