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catenin and Wnt/PCP activities, through interaction with the Dally-like homolog Knypek1 Medical Research Council Centre for Developmental Neurobiology, King’s College London, SE1 1UL London, United Kingdom; 2 Anatomy and Developmental Biology Department, University College London, WC1E 6BT London, United Kingdom; 3 Division of Molecular Embryology, German Cancer Research Center, D-69120 Heidelberg, Germany
Dickkopf-1 (Dkk1) is a secreted protein that negatively modulates the Wnt/
catenin pathway. Lack of Dkk1 function affects head formation in frog and mice, supporting the idea that Dkk1 acts as a "head inducer" during gastrulation. We show here that lack of Dkk1 function accelerates internalization and rostral progression of the mesendoderm and that gain of function slows down both internalization and convergence extension, indicating a novel role for Dkk1 in modulating these movements. The motility phenotype found in the morphants is not observed in embryos in which the Wnt/catenin pathway is overactivated, and that dominant-negative Wnt proteins are not able to rescue the gastrulation movement defect induced by absence of Dkk1. These data strongly suggest that Dkk1 is acting in a catenin independent fashion when modulating gastrulation movements. We demonstrate that the glypican 4/6 homolog Knypek (Kny) binds to Dkk1 and that they are able to functionally interact in vivo. Moreover, Dkk1 regulation of gastrulation movements is kny dependent. Kny is a component of the Wnt/planar cell polarity (PCP) pathway. We found that indeed Dkk1 is able to activate this pathway in both Xenopus and zebrafish. Furthermore, concomitant alteration of the catenin and PCP activities is able to mimic the morphant accelerated cell motility phenotype. Our data therefore indicate that Dkk1 regulates gastrulation movement through interaction with LRP5/6 and Kny and coordinated modulations of Wnt/catenin and Wnt/PCP pathways.
[Keywords: Dickkopf-1; HSPG; Wnt/PCP; gastrulation movements]
Received August 15, 2006; revised version accepted December 22, 2006.
E-MAIL corinne.houart{at}kcl.ac.uk; FAX 20-78486550.
Supplemental material is available at http://www.genesdev.org.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.406007
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