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First published online May 16, 2007
doi: 10.1242/10.1242/dev.000901

Development 134, 2051-2060 (2007)
Published by The Company of Biologists 2007
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Cerberus is a feedback inhibitor of Nodal asymmetric signaling in the chick embryo

Ana Teresa Tavares1,*, Sofia Andrade1, Ana Cristina Silva1,2 and José António Belo1,2,*

1 Instituto Gulbenkian de Ciência, 2781-901 Oeiras, Portugal.
2 Institute for Biotechnology and Bioengineering, Centro de Biomedicina Molecular e Estrutural, Universidade do Algarve, 8005-139 Faro, Portugal.

* Authors for correspondence (e-mails: atavares{at}igc.gulbenkian.pt; jbelo{at}ualg.pt)

Accepted 27 March 2007

The TGF-ß-related molecule Nodal plays an essential and conserved role in left-right patterning of the vertebrate embryo. Previous reports have shown that the zebrafish and mouse Cerberus-related proteins Charon and Cerberus-like-2 (Cerl-2), respectively, act in the node region to prevent the Nodal signal from crossing to the right side, whereas chick Cerberus (cCer) has an unclear function in the left-side mesoderm. In this study, we investigate the transcriptional regulation and function of cCer in left-right development. By analyzing the enhancer activity of cCer 5' genomic sequences in electroporated chick embryos, we identified a cCer left-side enhancer that contains two FoxH1 and one SMAD binding site. We show that these Nodal-responsive elements are necessary and sufficient for the activation of transcription in the left-side mesoderm. In transgenic mouse embryos, cCer regulatory sequences behave as in chick embryos, suggesting that the cis-regulatory sequences of Cerberus-related genes have diverged during vertebrate evolution. Moreover, our findings from cCer overexpression and knockdown experiments indicate that cCer is a negative-feedback regulator of Nodal asymmetric signaling. We propose that cCer and mouse Cerl-2 have evolved distinct regulatory mechanisms but retained a conserved function in left-right development, which is to restrict Nodal activity to the left side of the embryo.

Key words: Cerberus, FoxH1, Nodal signaling, Left-right asymmetry, Transcriptional regulation, Chick, Mouse


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Left-right patterning de-mystified

Development 2007 134: e1101. [Full Text]  





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