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Vol. 20, Issue 3, 924-936, February 1, 2009

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The Extracellular Domain of Lrp5/6 Inhibits Noncanonical Wnt Signaling In Vivo

Vitezslav Bryja^*,,, Emma R. Andersson^*,, Alexandra Schambony^,,||, Milan Esner^¶,#, Lenka Bryjová^*,, Kristin K. Biris^@, Anita C. Hall^*,**, Bianca Kraft, Lukas Cajanek^*, Terry P. Yamaguchi^@, Margaret Buckingham^¶, and Ernest Arenas^*

*Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Center for Developmental Biology and Regenerative Medicine, Karolinska Institute, SE-171 77 Stockholm, Sweden; Zoologisches Institut II, Universität Karlsruhe (TH), D-76131 Karlsruhe, Germany; ^¶Centre National de la Recherche Scientifique Unité de Recherche Associée 2578, Department of Developmental Biology, Pasteur Institute, 75 724 Paris Cedex 15, France; ^@Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702; and Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, 601 77, Brno, Czech Republic and Institute of Experimental Biology, Faculty of Science, Masaryk University, 602 00, Brno, Czech Republic

Submitted July 11, 2008; Revised November 20, 2008; Accepted November 21, 2008
Monitoring Editor: Kunxin Luo

Lrp5/6 are crucial coreceptors for Wnt/β-catenin signaling, a pathway biochemically distinct from noncanonical Wnt signaling pathways. Here, we examined the possible participation of Lrp5/6 in noncanonical Wnt signaling. We found that Lrp6 physically interacts with Wnt5a, but that this does not lead to phosphorylation of Lrp6 or activation of the Wnt/β-catenin pathway. Overexpression of Lrp6 blocks activation of the Wnt5a downstream target Rac1, and this effect is dependent on intact Lrp6 extracellular domains. These results suggested that the extracellular domain of Lrp6 inhibits noncanonical Wnt signaling in vitro. In vivo, Lrp6–/– mice exhibited exencephaly and a heart phenotype. Surprisingly, these defects were rescued by deletion of Wnt5a, indicating that the phenotypes resulted from noncanonical Wnt gain-of-function. Similarly, Lrp5 and Lrp6 antisense morpholino-treated Xenopus embryos exhibited convergent extension and heart phenotypes that were rescued by knockdown of noncanonical XWnt5a and XWnt11. Thus, we provide evidence that the extracellular domains of Lrp5/6 behave as physiologically relevant inhibitors of noncanonical Wnt signaling during Xenopus and mouse development in vivo.

These authors contributed equally to this work.

Present addresses: ^||Developmental Biology Unit, Department of Biology, University of Erlangen-Nuremberg, Staudtstrasse 5, 91058 Erlangen, Germany;

^#Max-Planck Institute of Molecular Cell Biology and Genetics, Screening facility, Pfotenhauerstrasse 108, D-01307 Dresden, Germany;

**Division of Cell and Molecular Biology, Imperial College London, United Kingdom.

Address correspondence to: Vitezslav Bryja (bryja{at}sci.muni.cz) or Ernest Arenas (ernest.arenas{at}ki.se)

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