Left–right asymmetry in the vertebrate embryo: from early information to higher-level integration

Key Points The left–right asymmetrical placement of internal organs that characterizes the vertebrate body plan is established during embryogenesis by complex genetic and epigenetic cascades. In all vertebrates that have been analysed so far, the expression of transcripts that encode the transforming growth factor-β (TGFB)-like signal NODAL is restricted to the left lateral plate mesoderm and this correlates with the establishment of proper left–right organ asymmetries. The embryo node (the organizer in Xenopus laevis , Hensen's node in birds and mammals) or its derivatives (Kupffer's vesicle in teleost fish) have key roles as organizing centres for the determination of left–right visceral asymmetries. In the mouse, the rotation of monocilia that project from the ventral side of the node creates a leftward flow of extracellular fluid that is necessary for proper left–right patterning (the nodal flow). Recent experimental and mathematical studies have shown that this directional flow can be generated de novo by cilia rotation in the absence of pre-existing laterality cues. Therefore, the nodal flow could be the initial symmetry-breaking event in the mouse embryo. Recent reports also show that the nodal flow takes place in embryos other than the mouse, including those of zebrafish, medaka fish and the rabbit. At least in zebrafish, the nodal flow is required for normal left–right asymmetrical patterning. We discuss the possibility that the nodal flow might amplify pre-existing laterality cues, rather than generate left–right asymmetry de novo , because further requirements for left–right patterning have been identified (at least in the zebrafish) that predate the establishment of the nodal flow. With the exception of the mouse, early requirements for correct left–right patterning have been identified in all the other main vertebrate model organisms ( X. laevis , chicks and zebrafish), including gap junction communications, differences in H + /K + -ATPase activity, asymmetrical gene expression, and Notch signalling. Data from various model organisms might provide insights into how these mechanisms relate to each other. Recent evidence shows that the mechanisms that control left–right asymmetries in inner organ placement and those that generate the bilaterally symmetrical outer body wall are integrated at the level of the node. How left–right asymmetries are established in vertebrate embryos has fascinated developmental biologists for decades. Recent evidence