Figure 9. Model for establishment of left-right asymmetry by reciprocal signaling between the ectoderm and the endomesoderm.

A, At midgastrula stage, nodal is expressed asymmetrically in endodermal cells on the right side under the influence of both positive (FGF and BMP signaling) and negative (signal X) inputs. At this stage, nodal is also expressed symmetrically in the ventral ectoderm. In contrast, univin is expressed more laterally in the presumptive ciliary band ectoderm and throughout the endoderm. As a consequence, the nodal and univin territories only partially overlap in the archenteron and in two ectodermal regions flanking the presumptive stomodeum (purple color). At this stage, while expression of nodal in the ventral ectoderm vanishes, asymmetrical Nodal+Univin signaling on the right side of the archenteron induces nodal expression in the lateral right ectoderm that expresses univin creating a novel Nodal+Univin expressing signaling center on the right side. The reaction-diffusion mechanism between Nodal and Lefty stabilizes nodal expression on the right side and prevents its expansion to the rest of the embryo. B, Summary diagrams of the experiments. Both the loss of nodal expression in the endoderm caused by inhibition of the FGF or BMP pathways or the bilateralisation of nodal expression in the endoderm caused by inhibition of Notch signaling, randomize nodal expression in the ectoderm at pluteus stage. In the endoderm, FGF/ERK positively regulates nodal expression on the right side while unidentified signals coming from the mesoderm induced by Delta/Notch signaling negatively regulate nodal expression on the left side of the archenteron. The window during which SU5402 and UO126 are effective at perturbing left-right asymmetry extends from fertilization to mesenchyme blastula/gastrula stage (green shading). H⁺/K⁺-ATPase acts on Delta/Notch signaling to regulate left-right asymmetry. The window during which DAPT (red shading) and omeprazole (blue shading) are effective on left-right asymmetry extends from egg up to the early blastula stage. Inhibition of Nodal or BMP signaling in the endomesoderm randomizes nodal expression in ectoderm. Injection of nodal mRNA alone fails to rescue left-right asymmetry and pitx2 expression in embryos previously injected with a nodal morpholino but coinjection of nodal+univin mRNAs efficiently rescues pitx2 expression in the coelomic pouch and ciliary band. In most of these embryos, pitx2 is expressed more strongly on the right side. An, animal pole; Veg, vegetal pole.