The extracellular domain of Lrp5/6 inhibits noncanonical Wnt signaling in vivo.
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.
Bryja
Vitezslav
V
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Center for Developmental Biology and Regenerative Medicine, Karolinska Institute, SE-171 77 Stockholm, Sweden. bryja@sci.muni.cz
Andersson
Emma R
ER
Schambony
Alexandra
A
Esner
Milan
M
Bryjová
Lenka
L
Biris
Kristin K
KK
Hall
Anita C
AC
Kraft
Bianca
B
Cajanek
Lukas
L
Yamaguchi
Terry P
TP
Buckingham
Margaret
M
Arenas
Ernest
E
D000818:Animals; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000196:embryology / Q000378:metabolism; D006579:Heterozygote; D026502:LDL-Receptor Related Proteins / Q000737:chemistry* / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D008817:Mice, Mutant Strains; D009436:Neural Tube Defects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000737:chemistry* / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein; D014981:Xenopus / Q000196:embryology / Q000378:metabolism; D029867:Xenopus Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; D016376:Oligonucleotides, Antisense; D011973:Receptors, LDL; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D029867:Xenopus Proteins; D051176:beta Catenin; D020830:rac1 GTP-Binding Protein