Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex.
Vertebrate Wnt proteins activate several distinct pathways. Intrinsic differences among Wnt ligands and Frizzled (Fzd) receptors, and the availability of pathway-specific coreceptors, LRP5/6, and Ror2, affect pathway selection. Here, we show that a secreted glycoprotein, Cthrc1, is involved in selective activation of the planar cell polarity (PCP) pathway by Wnt proteins. Although Cthrc1 null mutant mice appeared normal, the introduction of a heterozygous mutation of a PCP gene, Vangl2, resulted in abnormalities characteristic of PCP mutants. In HEK293T cells, Cthrc1 activated the PCP pathway but suppressed the canonical pathway. Cell-surface-anchored Cthrc1 bound to Wnt proteins, Fzd proteins, and Ror2 and enhanced the interaction of Wnt proteins and Fzd/Ror2 by forming the Cthrc1-Wnt-Fzd/Ror2 complex. Consistent with this, Ror2 mutant mice also showed PCP-related abnormalities in the inner ear. These results suggest that Cthrc1 is a Wnt cofactor protein that selectively activates the Wnt/PCP pathway by stabilizing ligand-receptor interaction.
Yamamoto
Shinji
S
Laboratory for Embryonic Induction, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Nishimura
Osamu
O
Misaki
Kazuyo
K
Nishita
Michiru
M
Minami
Yasuhiro
Y
Yonemura
Shigenobu
S
Tarui
Hiroshi
H
Sasaki
Hiroshi
H
D000818:Animals; D002460:Cell Line; D016764:Cell Polarity; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006199:Hair Cells, Auditory, Inner / Q000166:cytology; D006801:Humans; D007668:Kidney / Q000166:cytology; D007763:Lac Operon / Q000235:genetics; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D011995:Recombination, Genetic; D015398:Signal Transduction; D014018:Tissue Distribution; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
C530500:Cthrc1 protein, mouse; C502427:Cthrc1 protein, rat; D016326:Extracellular Matrix Proteins; D051157:Frizzled Receptors; D006023:Glycoproteins; D008024:Ligands; C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse