Abstract
SummaryDespite their burden and impact, most congenital defects remain poorly understood by lack of knowledge of the embryological mechanisms. Here, we identifyGreb1lmutants as the first mouse model of criss-cross 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 specific features of partial deficiency in retinoic acid signalling, suggesting that GREB1L is a novel modulator of this signalling. Spatio-temporal gene mapping and cross-correlated transcriptomic analyses further reveal the role ofGreb1lin maintaining a pool of precursor cells during heart tube elongation, by controlling ribosome biogenesis and cell differentiation. Growth arrest and malposition of the outflow tract are predictive of abnormal tube remodelling in mutants. Our work on a rare cardiac malformation opens novel perspectives on the origin of a broader spectrum of congenital defects associated withGREB1Lin humans.HighlightsGreb1linactivation is the first model of criss-cross heartGrowth arrest of the outflow tract and reduced pole distance are predictive of the torsion of the atrioventricular canal, and also account for associated defects of supero-inferior ventricles and malposition of the great vesselsVentricle position needs to be maintained after heart loopingGREB1L, which is associated in humans with a spectrum of congenital defects, is required to maintain precursor cells, by promoting ribosome biogenesis and restricting cell differentiation.GREB1L is a novel factor involved in retinoic acid signalling.In BriefGREB1Lis associated with a spectrum of congenital defects in humans. Bernheim et al now uncover its function in maintaining a reservoir of precursor cells. Inactivation ofGreb1lin the mouse impairs the elongation of the heart tube leading to criss-cross heart with supero-inferior ventricles.
Publisher
Cold Spring Harbor Laboratory