Cthrc1 Selectively Activates the Planar Cell Polarity Pathway of Wnt Signaling by Stabilizing the Wnt-Receptor Complex

• Published in: Developmental cell 2008-07, Vol.15 (1), p.23-36
• Main Authors: Yamamoto, Shinji, Nishimura, Osamu, Misaki, Kazuyo, Nishita, Michiru, Minami, Yasuhiro, Yonemura, Shigenobu, Tarui, Hiroshi, Sasaki, Hiroshi
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell Line; Cell physiology; Cell Polarity; Cell receptors; Cell structures and functions; DEVBIO; Embryo, Mammalian; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Frizzled Receptors - genetics; Frizzled Receptors - metabolism; Fundamental and applied biological sciences. Psychology; Glycoproteins - genetics; Glycoproteins - metabolism; Hair Cells, Auditory, Inner - cytology; Humans; Kidney - cytology; Lac Operon - genetics; Ligands; Mice; Mice, Knockout; Miscellaneous; Molecular and cellular biology; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptor Tyrosine Kinase-like Orphan Receptors; Recombination, Genetic; Signal Transduction; SIGNALING; Tissue Distribution; Wnt Proteins - genetics; Wnt Proteins - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2008.05.007

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.