Transient Nodal signalling in left precursors coordinates opposed asymmetries shaping the heart loop

Abstract

The secreted factor Nodal has been shown to be a major left determinant. Although it is associated with severe congenital heart defects, its role in heart morphogenesis has remained poorly understood. Here, we report that Nodal is transiently active in precursors of the mouse heart tube poles, before the morphological changes of heart looping. In conditional mutants, we show that Nodal is not required to initiate asymmetric morphogenesis. We provide evidence of a heart-specific random generator of asymmetry that is independent of Nodal. Using 3D quantifications and simulations, we demonstrate that Nodal functions as a bias of this mechanism: it is required to amplify and coordinate opposed left-right asymmetries at the heart tube poles, thus generating a robust helical shape. We identify downstream effectors of Nodal signalling, regulating asymmetries in cell proliferation, cell differentiation and extra-cellular matrix composition. Our work provides novel insight into how Nodal regulates asymmetric organogenesis.

Mesoderm patterning by a dynamic gradient of retinoic acid signalling

“…However, there does not seem to be a linear relationship between dose and phenotype, when deficiency and excess lead to similar phenotypes (table 1), which is similar to other morphogen gradients [2]. Recent developments of more quantitative measures of RA signalling [17], three-dimensional imaging of signalling [104] and royalsocietypublishing.org/journal/rstb Phil. Trans.…”

“…The left-right asymmetry of the heart is disrupted upon RA or FGF deficiency: looping defects have been reported in Por, Fgf8 and Aldh1a2 mutant embryos [29,99,100], and misaligned ventricles in Rdh10 mutant fetuses [101]. Fgf8;Mesp1 Cre/+ and Fgf8;Mef2cAHF-Cre conditional mutants [100] exhibit transposition of the great arteries and double outlet right ventricle, and are reminiscent of defective NODAL signalling [102][103][104]. The depletion of RERE, shown as a transcriptional cofactor of the RA receptor RAR in the presomitic mesoderm, also leads to looping defects [105].…”

Making the Right Loop for the heart

“…In the current issue of Developmental Cell, the same group reports how LR asymmetric Nodal signals regulate normal heart looping (Desgrange et al, 2020). First, the lineage of cells that expressed Nodal at early stages was found to be distributed on the left side of the outflow and inflow tracts, but not in the ventricles, during looping.…”