Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex

Dev Cell. 2008 Jul;15(1):23-36. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Polarity
  • Embryo, Mammalian
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Frizzled Receptors / genetics
  • Frizzled Receptors / metabolism*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Hair Cells, Auditory, Inner / cytology
  • Humans
  • Kidney / cytology
  • Lac Operon / genetics
  • Ligands
  • Mice
  • Mice, Knockout
  • 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*
  • Tissue Distribution
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*


  • Cthrc1 protein, mouse
  • Cthrc1 protein, rat
  • Extracellular Matrix Proteins
  • Frizzled Receptors
  • Glycoproteins
  • Ligands
  • Ltap protein, mouse
  • Nerve Tissue Proteins
  • Wnt Proteins
  • Receptor Protein-Tyrosine Kinases
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • Ror2 protein, mouse