Abstract
The 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.
Highlights
Establishment of the left-right (L-R) axis is fundamental for morphogenesis of visceral organs (Hamada et al, 2002; Shiratori and Hamada, 2006)
Given that Nodal expression in the lateral plate mesoderm (LPM) is induced by Nodal from the node (Brennan et al, 2002; Saijoh et al, 2003; Oki et al, 2007), we first examined the expression of Nodal and Cerl2, which encodes a
If the balance between Nodal and Cerl2 at the node is a key determinant of the sidedness of Nodal expression in the LPM, the expression pattern of Nodal in the LPM of inv/inv;Cerl2–/– embryos would be expected to be subject to the status of Nodal expression in the node
Summary
Establishment of the left-right (L-R) axis is fundamental for morphogenesis of visceral organs (Hamada et al, 2002; Shiratori and Hamada, 2006). The L-R axis of the mouse embryo is established by successive processes that begin with a leftward flow of fluid on the ventral surface of the node (nodal flow). Positive and negative regulatory loops amplify the small difference in gene expression in the node to generate the robust expression of Nodal in the left LPM (Nakamura et al, 2006). After Nodal expression appears in the left LPM near the node, the positive regulatory loop extends the Nodal expression domain to the entire left LPM (Norris et al, 2002; Yamamoto et al, 2003; Nakamura et al, 2006).
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