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- Reversal of left-right asymmetry induced by aberrant nodal signaling in the node of mouse embryosPublication . Oki, Shinya; Kitajima, Keiko; Marques, Sara; Belo, José A.; Yokoyama, Takahiko; Hamada, Hiroshi; Meno, ChikaraThe node at the anterior tip of the primitive streak serves as an initial generator of the left-right (L-R) axis in mammalian embryos. We now show that a small disturbance in molecular signaling at the node is responsible for the L-R reversal of visceral organs in the inv mutant mouse. In the node of wild-type embryos, the expression of Nodal and Cerl2 (Dand5), which encodes an inhibitor of Nodal, is asymmetric, with the level of Nodal expression being higher on the left side and that of Cerl2 expression higher on the right. In inv/inv embryos, however, a localized reduction in the level of Cerl2 expression results in upregulation of the Nodal signal and a consequent induction of Lefty expression in the node. The ectopic expression of Lefty1 delays the onset of Nodal expression in the lateral plate mesoderm. L-R asymmetry of Cerl2 expression in the node also becomes reversed in a manner dependent on the Nodal signal. Nodal expression in the lateral plate mesoderm then appears on the right side, probably reflecting the balance between Nodal and Cerl2 in the node. The inhibition of Cerl2 expression by the Nodal signal suggests a mechanism for amplification of the cue for L-R asymmetry provided by nodal flow and for stabilization of asymmetric gene expression around the node. In inv/inv embryos, this system may function in reverse as a result of ectopic production of Lefty, which inhibits the Nodal signal on the left side in a manner dependent on leftward nodal flow.
- The activity of the Nodal antagonist Cerl-2 in the mouse node is required for correct L/R body axisPublication . Marques, Sara; Borges, Ana; Silva, Ana Cristina; Freitas, Sandra; Cordenonsi, M.; Belo, José A.Correct establishment of the left/right (L/R) body asymmetry in the mouse embryo requires asymmetric activation of the evolutionarily conserved Nodal signaling cascade in the left lateral plate mesoderm (L-LPM). Furthermore, the presence of Nodal in the node is essential for its own expression in the L-LPM. Here, we have characterized the function of cerl-2, a novel Nodal antagonist, which displays a unique asymmetric expression on the right side of the mouse node. cerl-2 knockout mice display multiple laterality defects including randomization of the L/R axis. These defects can be partially rescued by removing one nodal allele. Our results demonstrate that Cerl-2 plays a key role in restricting the Nodal signaling pathway toward the left side of the mouse embryo by preventing its activity in the right side.