Interaction between Wnt and TGF-β signalling pathways during formation of Spemann's organizer

Members of the Wnt and TGF-β superfamilies regulate both cell fate and proliferation during development and tissue maintenance. In the early amphibian embryo, the Wnt and TGF-β superfamily signalling cascades are required for the establishment of a dorsal signalling centre, Spemann's organizer. Intracellular proteins of both pathways, upon activation, translocate to the nucleus to participate in transcription. Here we show that β-catenin and Lef1/Tcf, which are downstream components of the Wnt signalling cascade, form a complex with Smad4, an essential mediator of signals initiated by members of the TGF-β growth factor superfamily. In Xenopus, this interaction directly and synergistically affects expression of the twin (Xtwn) gene during formation of the organizer. This is, to our knowledge, the first demonstration of a physical interaction between TGF-β and Wnt signalling components in vivo.

[1]  Mariann Bienz,et al.  LEF-1, a Nuclear Factor Coordinating Signaling Inputs from wingless and decapentaplegic , 1997, Cell.

[2]  H. Theisen,et al.  Developmental territories created by mutual antagonism between Wingless and Decapentaplegic. , 1996, Development.

[3]  P. Hoodless,et al.  Dominant-negative Smad2 mutants inhibit activin/Vg1 signaling and disrupt axis formation in Xenopus. , 1999, Developmental biology.

[4]  G. Nolan,et al.  The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that activates through NF-kappa B p50 homodimers. , 1993, Genes & development.

[5]  T. Watabe,et al.  Molecular mechanisms of Spemann's organizer formation: conserved growth factor synergy between Xenopus and mouse. , 1995, Genes & development.

[6]  Ken W. Y. Cho,et al.  Molecular nature of Spemann's organizer: the role of the Xenopus homeobox gene goosecoid , 1991, Cell.

[7]  R. Moon,et al.  BMP-2/-4 and Wnt-8 cooperatively pattern the Xenopus mesoderm , 1998, Mechanisms of Development.

[8]  Ken W. Y. Cho,et al.  Cellular interpretation of multiple TGF-beta signals: intracellular antagonism between activin/BVg1 and BMP-2/4 signaling mediated by Smads. , 1997, Development.

[9]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[10]  L. Dobens,et al.  Medea is a Drosophila Smad4 homolog that is differentially required to potentiate DPP responses. , 1998, Development.

[11]  Ken W. Y. Cho,et al.  The Xenopus homeobox gene twin mediates Wnt induction of goosecoid in establishment of Spemann's organizer. , 1997, Development.

[12]  J. Massagué,et al.  Partnership between DPC4 and SMAD proteins in TGF-β signalling pathways , 1996, Nature.

[13]  C. Larabell,et al.  Establishment of the Dorso-ventral Axis in Xenopus Embryos Is Presaged by Early Asymmetries in β-Catenin That Are Modulated by the Wnt Signaling Pathway , 1997, The Journal of cell biology.

[14]  R. Grosschedl,et al.  LEF-1/TCF proteins mediate wnt-inducible transcription from the Xenopus nodal-related 3 promoter. , 1997, Developmental biology.

[15]  W. Brook,et al.  Antagonistic Interactions Between Wingless and Decapentaplegic Responsible for Dorsal-Ventral Pattern in the Drosophila Leg , 1996, Science.

[16]  R. Moon,et al.  The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. , 1996, Genes & development.

[17]  B. Hogan,et al.  DVR-4 (bone morphogenetic protein-4) as a posterior-ventralizing factor in Xenopus mesoderm induction. , 1992, Development.

[18]  Hiroyuki Miyoshi,et al.  Intestinal Tumorigenesis in Compound Mutant Mice of both Dpc4(Smad4) and Apc Genes , 1998, Cell.

[19]  Yigong Shi,et al.  Crystal Structure of a Smad MH1 Domain Bound to DNA Insights on DNA Binding in TGF-β Signaling , 1998, Cell.

[20]  R. Nusse,et al.  Wnt signaling: a common theme in animal development. , 1997, Genes & development.

[21]  J. Gurdon,et al.  Cooperation between the activin and Wnt pathways in the spatial control of organizer gene expression. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Frank McCormick,et al.  β-Catenin regulates expression of cyclin D1 in colon carcinoma cells , 1999, Nature.

[23]  R. Moon,et al.  A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus. , 1997, Genes & development.

[24]  R. Moon,et al.  From cortical rotation to organizer gene expression: toward a molecular explanation of axis specification in Xenopus , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[25]  Kohei Miyazono,et al.  TGF-β signalling from cell membrane to nucleus through SMAD proteins , 1997, Nature.

[26]  J. Massagué.  TGF-beta signal transduction. , 1998, Annual review of biochemistry.

[27]  J. Gerhart,et al.  Formation and function of Spemann's organizer. , 1997, Annual review of cell and developmental biology.

[28]  R. Moon,et al.  Interactions between Xwnt-8 and Spemann organizer signaling pathways generate dorsoventral pattern in the embryonic mesoderm of Xenopus. , 1993, Genes & development.