The extracellular domain of Lrp5/6 inhibits noncanonical Wnt signaling in vivo
Autor: | Lenka Bryjova, Terry P. Yamaguchi, Margaret Buckingham, Ernest Arenas, Milan Esner, Anita C. Hall, Vitezslav Bryja, Emma R. Andersson, Kristin K. Biris, Lukas Cajanek, Alexandra Schambony, Bianca Kraft |
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Rok vydání: | 2008 |
Předmět: |
Heart Defects
Congenital rac1 GTP-Binding Protein Heterozygote Beta-catenin Embryo Nonmammalian Xenopus Embryonic Development Xenopus Proteins Wnt-5a Protein Mice Animals Neural Tube Defects Molecular Biology LDL-Receptor Related Proteins beta Catenin biology Convergent extension Wnt signaling pathway LRP6 LRP5 Heart Cell Biology Articles Oligonucleotides Antisense biology.organism_classification Molecular biology Mice Mutant Strains Protein Structure Tertiary Enzyme Activation Wnt Proteins Low Density Lipoprotein Receptor-Related Protein-5 Phenotype Receptors LDL Low Density Lipoprotein Receptor-Related Protein-6 biology.protein Phosphorylation Signal transduction Gene Deletion Protein Binding Signal Transduction |
Zdroj: | Molecular biology of the cell. 20(3) |
ISSN: | 1939-4586 |
Popis: | 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. |
Databáze: | OpenAIRE |
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