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First published online November 26, 2007
doi: 10.1242/10.1242/dev.000026

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Ttrap is an essential modulator of Smad3-dependent Nodal signaling during zebrafish gastrulation and left-right axis determination

Camila V. Esguerra^1,2,,*, Luc Nelles^3,4,, Liesbeth Vermeire^3,4, Abdelilah Ibrahimi^3,4,, Alexander D. Crawford^1,2,¶, Rita Derua⁵, Els Janssens^1,2, Etienne Waelkens⁵, Peter Carmeliet^1,2, Desiré Collen^1,2 and Danny Huylebroeck^3,4,*

¹ Center for Transgene Technology and Gene Therapy, VIB, Herestraat 49, B-3000 Leuven, Belgium.
² Department of Molecular and Cellular Medicine, KULeuven, Herestraat 49, B-3000 Leuven, Belgium.
³ Laboratory of Molecular Biology, Department of Molecular and Developmental Genetics, VIB, Herestraat 49, B-3000 Leuven, Belgium.
⁴ Department of Human Genetics, KULeuven, Herestraat 49, B-3000 Leuven, Belgium.
⁵ Division of Biochemistry, Department of Molecular Cell Biology, KULeuven, Herestraat 49, B-3000 Leuven, Belgium.

^* Authors for correspondence (e-mails: camila.esguerra{at}med.kuleuven.be; danny.huylebroeck{at}med.kuleuven.be)

Accepted 16 September 2007

During vertebrate development, signaling by the TGFβ ligand Nodal is critical for mesoderm formation, correct positioning of the anterior-posterior axis, normal anterior and midline patterning, and left-right asymmetric development of the heart and viscera. Stimulation of Alk4/EGF-CFC receptor complexes by Nodal activates Smad2/3, leading to left-sided expression of target genes that promote asymmetric placement of certain internal organs. We identified Ttrap as a novel Alk4- and Smad3-interacting protein that controls gastrulation movements and left-right axis determination in zebrafish. Morpholino-mediated Ttrap knockdown increases Smad3 activity, leading to ectopic expression of snail1a and apparent repression of e-cadherin, thereby perturbing cell movements during convergent extension, epiboly and node formation. Thus, although the role of Smad proteins in mediating Nodal signaling is well-documented, the functional characterization of Ttrap provides insight into a novel Smad partner that plays an essential role in the fine-tuning of this signal transduction cascade.

Key words: Alk4, E-cadherin, Gastrulation, Left-right asymmetry, Node, Smad

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