A spatiotemporal barrier formed by Follistatin is required for left-right patterning

How left-right (LR) asymmetry emerges in a patterning field along the anterior-posterior axis remains an unresolved problem in developmental biology. Left-biased Nodal emanat-ing from the LR organizer propagates from posterior to anterior (PA) and establishes the LR pattern of the whole embryo. However, little is known about the regulatory mech-anism of the PA spread of Nodal and its asymmetric activation in the forebrain. Here, we identify bilaterally expressed Follistatin (Fst) as a regulator blocking the propagation of the zebrafish Nodal ortholog Southpaw (Spaw) in the right lateral plate mesoderm (LPM), and restricting Spaw transmission in the left LPM to facilitate the establishment of a robust LR asymmetric Nodal patterning. In addition, Fst inhibits the Activin-Nodal signaling pathway in the forebrain thus preventing Nodal activation prior to the arrival, at a later time, of Spaw emanating from the left LPM. This contributes to the orderly prop-agation of asymmetric Nodal activation along the PA axis. The LR regulation function of Fst is further confirmed in chick and frog embryos. Overall, our results suggest that a robust LR patterning emerges by counteracting a Fst barrier formed along the PA axis.SignificanceThe left-right patterning of vertebrate embryos relies on an orderly propagation of the asymmetric Nodal signaling from posterior to anterior. This requires a left-right organizer (LRO) that is located at the posterior tip of the embryo to break the bilateral symmetry, as well as a midline barrier that prevents Nodal from diffusing along the left-right direction. The current study identifies a new barrier, which is set up by Follistatin (Fst) and expressed bilaterally. This barrier gates the propagation of the asymmetric Nodal activity toward the anterior to ensure a proper left-right patterning outcome throughout the entire embryo including the forebrain.