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Despite an outwardly bilaterally symmetrical appearance, most internal organs of vertebrates display considerable left-right (LR) asymmetry in their anatomy and physiology. The orientation of LR asymmetry with respect to the dorsoventral and anteroposterior body axes is invariant such that fewer than 1 in 10,000 individuals exhibit organ reversals. The stereotypic orientation of LR asymmetry is ensured by distinct left- and right-side signal transduction pathways that are initiated by divergent members of the transforming growth factor-β (TGF-β) superfamily of secreted proteins. During early embryogenesis, the TGF-β-like protein Nodal (or a Nodal-related ortholog) is expressed by the left lateral plate mesoderm and provides essential LR cues to the developing organs. In chick embryos at least, bone morphogenetic protein (BMP) signaling is active on the right side of the embryo and must be inhibited on the left in order for Nodal to be expressed. Thus, at a key point in the determination of LR asymmetry, left-sided signaling is mediated by the transcription factors Smad2 and Smad3 (regulated by Nodal), whereas signaling on the right depends on Smad1 and Smad5 (which are regulated by BMP). This review summarizes the considerable progress that has been made in recent years in understanding the complex network of feedback and feedforward circuitry that regulates both the left- and right-sided pathways. Also discussed is the problem of how signal transduction mediated by the Smad proteins can pattern LR asymmetry without interfering with coincident dorsoventral patterning, which relies on the same Smad proteins.