Functional and biochemical interactions of Wnts with FrzA, a secreted Wnt antagonist.
Wnts are highly conserved developmental regulators that mediate inductive signaling between neighboring cells and participate in the determination of embryonic axes. Frizzled proteins constitute a large family of putative transmembrane receptors for Wnt signals. FrzA is a novel protein that shares sequence similarity with the extracellular domain of Frizzled. The Xenopus homologue of FrzA is dynamically regulated during early development. At the neurula stages, XfrzA mRNA is abundant in the somitic mesoderm, but later becomes strongly expressed in developing heart, neural crest derivatives, endoderm, otic vesicle and other sites of organogenesis. To evaluate possible biological functions of FrzA, we analyzed its effect on early Xenopus development. Microinjection of bovine or Xenopus FrzA mRNA into dorsal blastomeres resulted in a shortened body axis, suggesting a block of convergent extension movements. Consistent with this possibility, FrzA blocked elongation of ectodermal explants in response to activin, a potent mesoderm-inducing factor. FrzA inhibited induction of secondary axes by Xwnt8 and human Wnt2, but not by Xdsh, supporting the idea that FrzA interferes with Wnt signaling. Furthermore, FrzA suppressed Wnt-dependent activation of the early response genes in ectodermal explants and in the marginal zone. Finally, immunoprecipitation experiments demonstrate that FrzA binds to the soluble Wingless protein in cell culture supernatants in vitro. Our results indicate that FrzA is a naturally occurring secreted antagonist of Wnt signaling.
Xu
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Department of Pathology, Harvard Medical School and Laboratory for Surgical Research, Children's Hospital, Boston, MA 02215, US.
D'Amore
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Sokol
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D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning; D002417:Cattle; D004475:Ectoderm / Q000166:cytology / Q000502:physiology; D004625:Embryo, Nonmammalian / Q000502:physiology*; D004627:Embryonic Induction; D005260:Female; D005307:Fertilization in Vitro; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D008845:Microinjections; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D051153:Wnt Proteins; D051154:Wnt2 Protein; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology*; D029961:Zebrafish Proteins; D000094742:Secreted Frizzled-Related Proteins
D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051153:Wnt Proteins; D051154:Wnt2 Protein; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C485538:SFRP1 protein, Xenopus; D000094742:Secreted Frizzled-Related Proteins; C117636:SFRP1 protein, human; C495244:WNT2 protein, human