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The novel Cer-like protein Caronte mediates the establishment of embryonic left–right asymmetry

Nature volume 401, pages 243–251 (1999)Cite this article

Abstract

In the chick embryo, left–right asymmetric patterns of gene expression in the lateral plate mesoderm are initiated by signals located in and around Hensen's node. Here we show that Caronte (Car), a secreted protein encoded by a member of the Cerberus/Dan gene family, mediates the Sonic hedgehog (Shh)-dependent induction of left-specific genes in the lateral plate mesoderm. Car is induced by Shh and repressed by fibroblast growth factor-8 (FGF-8). Car activates the expression of Nodal by antagonizing a repressive activity of bone morphogenic proteins (BMPs). Our results define a complex network of antagonistic molecular interactions between Activin, FGF-8, Lefty-1, Nodal, BMPs and Car that cooperate to control left–right asymmetry in the chick embryo.

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Figure 1: Expression of Car, Nodal and Lefty-1 during chick gastrulation.
Figure 2: Car acts downstream of Shh and upstream of Nodal and directs heart looping in the chick embryo.
Figure 3: Antagonism of BMPs by Car regulates Nodal expression.
Figure 4: Interaction of Car with BMPs: biochemical evidence and structural model.
Figure 5: FGF-8 and Activin regulate Car expression.
Figure 6: Interaction between Lefty-1 and Car during the establishment of left–right asymmetry.
Figure 7: cNKX3.2 is a novel target of the left–right signalling pathway.
Figure 8: Role of Car in the genetic cascade that determines left–right development.

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Acknowledgements

We thank J. Magallón for technical help; T. Brand, R. Evans, H. Hamada, C. Kintner, G. Rosenfeld, C. Stern, C. Tabin and members of P. E. Wright's group for discussions and for sharing unpublished observations; W. Vale and S. Choe for reagents; J. P. Fandl (for providing human Cerberus) and X. Wang (for technical help), both at Regeneron; J. Hurlé for scanning images; C. Parada for suggesting the name Caronte; and L. Hooks for help in preparing the manuscript. J.C. was supported by a Hoffmann Foundation Fellowship; J.P. was supported by a long-term EMBO Fellowship. This work was supported by grants from the G. Harold and Leila Y. Mathers Charitable Foundation and the NIH to J.C.I.B., who is a Pew Scholar.

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  1. Concepción Rodríguez Esteban, Javier Capdevila, Jaime Pascual and Ángel Ortiz: These authors contributed equally to this work

Authors and Affiliations

  1. The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, 92037, California, USA

    Concepción Rodríguez Esteban, Javier Capdevila & Juan Carlos Izpisúa Belmonte

  2. Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York, 10591, USA

    Aris N. Economides

  3. Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037, USA

    Jaime Pascual & Ángel Ortiz

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  1. Concepción Rodríguez Esteban
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Correspondence to Juan Carlos Izpisúa Belmonte.

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Esteban, C., Capdevila, J., Economides, A. et al. The novel Cer-like protein Caronte mediates the establishment of embryonic left–right asymmetry. Nature 401, 243–251 (1999). https://doi.org/10.1038/45738

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