ABSTRACT
The asymmetries of internal organs are consistently oriented along the left-right axis in all vertebrates, and perturbations of left-right orientation lead to significant congenital disease. We propose a model in which a "left-right coordinator" interacts with the Spemann organizer to coordinate the evolutionarily conserved three-dimensional asymmetries in the embryo. The Vg1 cell-signaling pathway plays a central role in left-right coordinator function. Antagonists of Vg1 alter left-right development; antagonists of other members of the TGFbeta family do not. Cell-lineage directed expression of Vg1 protein can fully invert the left-right axis (situs inversus), can randomize left-right asymmetries, or can "rescue" a perturbed left-right axis in conjoined twins to normal orientation (situs solitus), indicating that Vg1 can mimic left-right coordinator activity. These are the first molecular manipulations in any vertebrate by which the left-right axis can be reliably controlled.
Subject(s)
Embryo, Nonmammalian/physiology , Embryonic Induction , Glycoproteins/biosynthesis , Heart/embryology , Proteins , Activins , Animals , Carrier Proteins , Follistatin , Gene Expression Regulation, Developmental , Glycoproteins/antagonists & inhibitors , Inhibins/biosynthesis , Protein Biosynthesis , Signal Transduction , Transforming Growth Factor beta/biosynthesis , Xenopus/embryology , Xenopus ProteinsABSTRACT
In the development of the three-dimensional vertebrate body plan, the left-right axis is linked to the dorsoventral and anterioposterior axes. In humans, altered left-right development results in severe cardiovascular and visceral abnormalities in individuals and in conjoined twins. Although zygotically transcribed genes that are asymmetrically expressed have been identified, the mechanism by which left-right asymmetries are established during embryogenesis is unknown. Here we show that the Xenopus maternal gene Vg1, a member of the TGF-beta family of cell-signalling molecules which are implicated in dorsoanterior development, initiates left-right axis formation. Altered expression of Vg1 on the right side of 16-cell embryos or disruption of endogenous Vg1 signalling on the left side randomizes cardiac and visceral left-right orientation and alters expression of Xnr-1, a nodal-related molecular marker for left-right development. Furthermore, the orientation of the left-right axis in conjoined twins is dependent upon which cell-signalling molecule initiated twin formation and on whether the secondary axis is on the left or right side of the primary embryonic axis, implicating a molecular pathway leading to the formation of conjoined twins.
