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

Shinji Yamamoto; Osamu Nishimura; Kazuyo Misaki; Michiru Nishita; Yasuhiro Minami; Shigenobu Yonemura; Hiroshi Tarui; Hiroshi Sasaki

doi:10.1016/j.devcel.2008.05.007

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.

Authors

Shinji Yamamoto¹, Osamu Nishimura, Kazuyo Misaki, Michiru Nishita, Yasuhiro Minami, Shigenobu Yonemura, Hiroshi Tarui, Hiroshi Sasaki

Affiliation

¹ Laboratory for Embryonic Induction, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.

PMID: 18606138
DOI: 10.1016/j.devcel.2008.05.007

Abstract

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*

Substances

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