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First published online November 11, 2009
doi: 10.1242/10.1242/dev.039305

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Reversal of left-right asymmetry induced by aberrant Nodal signaling in the node of mouse embryos

Shinya Oki^1,*, Keiko Kitajima^1,*, Sara Marques², José António Belo², Takahiko Yokoyama³, Hiroshi Hamada^4, and Chikara Meno^1,4,

¹ Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
² IBB-Institute for Biotechnology and Bioengineering, Centro de Biomedicina Molecular e Estrutural, Universidade do Algarve, Campus de Gambelas, Faro, Portugal, and Instituto Gulbenkian de Ciência, 2781-901 Oeiras, Portugal
³ Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
⁴ Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan

Authors for correspondence (hamada{at}fbs.osaka-u.ac.jp; meno{at}dev.med.kyushu-u.ac.jp)

Accepted September 22, 2009

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.

Key words: Left-right axis, Node, Mouse, Nodal signal, inv

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