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

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. RNA-seq of wildtype or Nodal-deficient E8.5 embryonic microdissected cardiac region.分泌因子Nodal（Nodal）已被证实为关键的左侧发育决定因子。尽管其与严重的先天性心脏缺陷密切相关，但学界对其在心脏形态发生中的具体作用仍知之甚少。本研究发现，在心脏环化的形态学变化发生前，Nodal会在小鼠心管极区的前体细胞中瞬时激活。在条件性突变体实验中，我们证实Nodal并非启动不对称形态发生的必需因子。我们发现了一种不依赖于Nodal的心脏特异性不对称随机发生机制，并提供了相关实验证据。通过三维定量分析与模拟实验，我们证实Nodal作为该机制的偏置因子发挥功能：其可在心管极区放大并协调对立的左右不对称性，从而形成稳定的螺旋形态。我们鉴定出Nodal信号通路的下游效应因子，这些因子可调控细胞增殖、细胞分化及细胞外基质组成相关的不对称性变化。本研究为Nodal调控不对称器官发生的分子机制提供了全新的见解。本数据集涵盖野生型或Nodal缺陷型小鼠胚胎发育第8.5天（E8.5）显微切割心脏区域的RNA测序数据。