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

  1. Author:
    Bryja, V.
    Andersson, E. R.
    Schambony, A.
    Esner, M.
    Bryjova, L.
    Biris, K. K.
    Hall, A. C.
    Kraft, B.
    Cajanek, L.
    Yamaguchi, T. P.
    Buckingham, M.
    Arenas, E.
  2. Author Address

    Bryja, Vitezslav, Andersson, Emma R.; Bryjova, Lenka, Hall, Anita C.; Cajanek, Lukas, Arenas, Ernest] Karolinska Inst, Ctr Dev Biol & Regenerat Med, Mol Neurobiol Lab, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden. [Schambony, Alexandra, Kraft, Bianca] Univ Karlsruhe TH, Inst Zool 2, D-76131 Karlsruhe, Germany. [Esner, Milan, Buckingham, Margaret] Inst Pasteur, CNRS, Unite Rech Associee 2578, Dept Dev Biol, F-75724 Paris, France. [Biris, Kristin K.; Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Bryja, Vitezslav, Bryjova, Lenka] Acad Sci Czech Republic, Inst Biophys, Dept Cytokinet, Brno 60177, Czech Republic. [Bryja, Vitezslav, Bryjova, Lenka] Masaryk Univ, Fac Sci, Inst Expt Biol, Brno 60200, Czech Republic.
    1. Year: 2009
  1. Journal: Molecular Biology of the Cell
    1. 20
    2. 3
    3. Pages: 924-936
  2. Type of Article: Article
  1. Abstract:

    Lrp5/6 are crucial coreceptors for Wnt/beta-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/beta-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.

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External Sources

  1. PMID: 19056682

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