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Mol Biol Cell 2009 Feb 01;203:924-36. doi: 10.1091/mbc.e08-07-0711.
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The extracellular domain of Lrp5/6 inhibits noncanonical Wnt signaling in vivo.

Bryja V , Andersson ER , Schambony A , Esner M , Bryjová L , Biris KK , Hall AC , Kraft B , Cajanek L , Yamaguchi TP , Buckingham M , Arenas E .

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.

PubMed ID: 19056682
PMC ID: PMC2633404
Article link: Mol Biol Cell

Species referenced: Xenopus
Genes referenced: actl6a cdc42 ctnnb1 dvl2 dvl3 lrp5 lrp6 myc rac1 rhoa wnt11 wnt11b wnt3a wnt5a
Morpholinos: lrp5 MO1 lrp6 MO2 wnt11b MO1 wnt5a MO1

Article Images: [+] show captions
References [+] :
Andersson, Wnt5a regulates ventral midbrain morphogenesis and the development of A9-A10 dopaminergic cells in vivo. 2008, Pubmed