title: Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation.
abstract: Convergent extension movements during vertebrate gastrulation require a balanced activity of non-canonical Wnt signaling pathways, but the factors regulating this interplay on the molecular level are poorly characterized. Here we show that sFRP2, a member of the secreted frizzled-related protein (sFRP) family, is required for morphogenesis and papc expression during Xenopus gastrulation. We further provide evidence that sFRP2 redirects non-canonical Wnt signaling from Frizzled 7 (Fz7) to the receptor tyrosine kinase-like orphan receptor 2 (Ror2). During this process, sFRP2 promotes Ror2 signal transduction by stabilizing Wnt5a-Ror2 complexes at the membrane, whereas it inhibits Fz7 signaling, probably by blocking Fz7 receptor endocytosis. The cysteine-rich domain of sFRP2 is sufficient for Ror2 activation, and related sFRPs can substitute for this function. Notably, direct interaction of the two receptors via their cysteine-rich domains also promotes Ror2-mediated papc expression but inhibits Fz7 signaling. We propose that sFRPs can act as a molecular switch, channeling the signal input for different non-canonical Wnt pathways during vertebrate gastrulation.
authors.affiliation: From the Institute of Human Genetics, Department of Developmental Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Brinkmann
authors.affiliation: the Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, 76344 Karlsruhe, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mattes
authors.affiliation: From the Institute of Human Genetics, Department of Developmental Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.affiliation: the Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, 76344 Karlsruhe, Germany.
authors.forename: Anja I H
authors.initials: AI
authors.lastname: Hagemann
authors.affiliation: the Zoological Institute, Department of Cell and Developmental Biology, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany, and.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Gradl
authors.affiliation: the Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, 76344 Karlsruhe, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Scholpp
authors.affiliation: From the Institute of Human Genetics, Department of Developmental Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Steinbeisser
authors.affiliation: From the Institute of Human Genetics, Department of Developmental Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany, lilian.kaufmann@med.uni-heidelberg.de.
authors.forename: Lilian T
authors.initials: LT
authors.lastname: Kaufmann
authors.affiliation: the Centre of Organismal Studies, Department of Molecular Evolution and Genomics, University of Heidelberg, 69120 Heidelberg, Germany suat.oezbek@cos.uni-heidelberg.de.
authors.forename: Suat
authors.initials: S
authors.lastname: Özbek
mesh_terms: D000818:Animals; D005775:Gastrula; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000071818:Wnt-5a Protein / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D008565:Membrane Proteins; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D000071818:Wnt-5a Protein; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C492040:Fzd7 protein, Xenopus; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C515511:Sfrp2 protein, zebrafish; C085389:WNT5A protein, human; C085096:Wnt5a protein, Xenopus; C480282:Wnt5a protein, zebrafish; C470289:fzd7a protein, zebrafish; C078717:ROR2 protein, human; C000598273:Ror2 protein, Xenopus
keywords: Fz7; Ror2; Wnt signaling; Xenopus; development; embryo; papc; sFRP2; zebrafish