Abstract
Author SummarySuperficially, humans, like other vertebrates, are bilaterally symmetrical. Nonetheless, the internal configuration of visceral organs reveals a stereotypical asymmetry. For example, human hearts are generally located on the left and the liver on the right side within the body cavity. How this left-right asymmetry is established is an area of interest, for both intrinsic biological significance and its medical application. In the mouse, the initial event that breaks left-right symmetry occurs at the node, a specialized organ located in the midline of the developing embryo. Somehow this initial asymmetry leads to a cascade of events that results in the activation of a genetic circuit on the left side of the embryo, which then leads to asymmetric organ formation. Here we show that the laterality information that is generated at the node is transferred to the lateral extremity of the embryo across the gut endoderm, which is the precursor tissue of the respiratory and digestive tracts and associated organs such as lungs, liver, and pancreas. Sox17 mutant mouse embryos exhibit defects in gut endoderm formation and fail to establish left-right asymmetry. Analysis of the mutants reveals that gap junction coupling across the gut endoderm is the mechanism of left-right information relay from the midline site of symmetry breaking to the site of asymmetric organogenesis in mice.
Highlights
IntroductionThe elaboration of the major axes of the embryo (anteriorposterior, dorsal-ventral, and left-right) occurs at the time of gastrulation, the morphogenetic process that forms the primary germ layers (ectoderm, mesoderm, and definitive endoderm)
The elaboration of the major axes of the embryo occurs at the time of gastrulation, the morphogenetic process that forms the primary germ layers
The initial event that breaks left-right symmetry occurs at the node, a specialized organ located in the midline of the developing embryo
Summary
The elaboration of the major axes of the embryo (anteriorposterior, dorsal-ventral, and left-right) occurs at the time of gastrulation, the morphogenetic process that forms the primary germ layers (ectoderm, mesoderm, and definitive endoderm). By E8.5, equivalent to the ,4 somite stage, an asymmetric readout of this soon after widespread emVE and DE cell intercalation is complete, when node to LPM signal relay likely occurs. We demonstrated gap junctional coupling on both the left and right sides of the gut endoderm of wild-type embryos, but not in Sox mutants. Since Cx43 localization within the mesoderm was comparable in wild-type and mutant embryos, we concluded that LR signals must be propagated across the endoderm epithelium. Our studies revealed an absence of gap junctional coupling across cells at the midline in wild-type embryos, thereby providing the first functional visualization of a midline barrier in the mouse
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