MicroRNAs Establish the Right-Handed Dominance of the Heart Laterality Pathway in Vertebrates

Despite their external bilateral symmetry, vertebrates have internal left/right (L/R) asymmetries required for optimal organ function. BMP-induced epithelial to mesenchymal transition (EMT) in the lateral plate mesoderm (LPM) triggers L/R asymmetric cell movements toward the midline, higher from the right, which are crucial for heart laterality in vertebrates. However, how the L/R asymmetric levels of EMT factors are achieved is not known. Here, we show that the posterior-to-anterior Nodal wave upregulates several microRNAs (miRNAs) to transiently attenuate the levels of EMT factors (Prrx1a and Snail1) on the left LPM in a Pitx2-independent manner in the fish and mouse. These data clarify the role of Nodal in heart laterality and explain how Nodal and BMP exert their respective dominance on the left and right sides through the mutual inhibition of their respective targets, ensuring the proper balance of L/R information required for heart laterality and morphogenesis.