Cerberus–Nodal–Lefty–Pitx signaling cascade controls left – right asymmetry in amphioxus

Significance Some bilaterally symmetrical animals show genetically programmed differences between their left and right sides, for example the placement of the heart and viscera in humans and other vertebrates. We dissect the regulation of this in embryos of amphioxus, a close relative of vertebrates that develops extraordinary asymmetries as a larva. We demonstrate a system in which asymmetric expression of the signal gene Noda l is controlled by positive and negative feedback loops with its own inhibitors. When this system is disrupted, embryos develop mirror-image symmetry with two “left” sides or two “right” sides. Comparison with other animals shows how this complex regulatory mechanism has evolved by addition of new feedback regulation to a more ancient signaling interaction.