The activity of the Nodal antagonist Cerl-2 in the mouse node is required for correct L/R body axis

Abstract

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.Supplemental material is available at http://www.genesdev.org.

Xenopus nodal related-1 is indispensable only for left-right axis determination

“…Thus, this domain is regarded to be the organizing center of the left-right axis in the zebrafish embryo. Recently, mouse Cerberuslike 2 (Cerl-2; Dante) was identified and this molecule also plays a key role in restricting the Nodal signaling toward the left side by preventing its activity in the right side (Marques et al, 2004). In Xenopus embryos, expression of the gene coding for a member of Cerberus/Dan family such as Charon or Cerl-2 at the tail region has not yet been reported.…”

Secreted and Transmembrane Wnt Inhibitors and Activators

“…Rather, Cerberus-related proteins are key regulators of Nodal signaling and play an important role in the establishment of left -right asymmetry in the vertebrate embryo (Rodriguez Esteban et al 1999;Yokouchi et al 1999;Zhu et al 1999;Hashimoto et al 2004;Marques et al 2004;Tavares et al 2007;Vonica and Brivanlou 2007).…”

Hyperglycemia impairs left–right axis formation and thereby disturbs heart morphogenesis in mouse embryos

“…These results thus suggested that the amount of Nodal-GDF1 produced in the node is reduced in the high-glucose condition. Expression of Nodal in the left LPM requires the activity of Nodal in crown cells to be regulated in an L-R asymmetric manner, with Cerl2 playing an essential role in such regulation through suppression of Nodal activity (32,33,35). Cerl2 is expressed in crown cells, with the level of expression being higher on the right side.…”

“…Nodal produced in the crown cells of the node is required for the subsequent expression of Nodal in the left LPM (30,32,37). We therefore next examined whether the expression of Nodal-related genes, including Nodal, Gdf1, and Cerl2, was affected in the node of highglucose embryos.…”

“…First, Nodal produced by crown cells induces Nodal expression in the LPM (37). Second, the L-R asymmetric activity of Nodal in the node determines the side on which Nodal is expressed in the LPM (32,33,35). Notch signaling is required for Nodal expression in the node (46,47).…”