Frizzled-7 signalling controls tissue separation during Xenopus gastrulation
Abstract
Cell signalling through Frizzled receptors has evolved to considerable complexity within the metazoans. The Frizzled-dependent signalling cascade comprises several branches, whose differential activation depends on specific Wnt ligands, Frizzled receptor isoforms and the cellular context. In Xenopus laevis embryos, the canonical beta-catenin pathway contributes to the establishment of the dorsal-ventral axis. A different branch, referred to as the planar cell polarity pathway, is essential for cell polarization during elongation of the axial mesoderm by convergent extension. Here we demonstrate that a third branch of the cascade is independent of Dishevelled function and involves signalling through trimeric G proteins and protein kinase C (PKC). During gastrulation, Frizzled-7 (Fz7)-dependent PKC signalling controls cell-sorting behaviour in the mesoderm. Loss of zygotic Fz7 function results in the inability of involuted anterior mesoderm to separate from the ectoderm, which leads to severe gastrulation defects. This result provides a developmentally relevant in vivo function for the Fz/PKC pathway in vertebrates.
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Ca2+ can activate PKC which regulates the process of tissue separation during gastrulation via activation of the small GTPase CDC42.
“Ca2+ can also activate PKC which regulates the process of tissue separation during gastrulation via activation of the small GTPase CDC42.100”
From Wnt signal transduction pathways (2008) · cites this paper as [100]
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Wnt signal transduction pathways
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Bengochea, A., de Souza, M. M., Lefrançois, L., Le Roux, E., Galy, O., Chemin, I., Kim, M., Wands, J. R., Trepo, C., Hainaut, P., et al. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604422 · Cited by 215 · see citing works
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Increasingly complex: New players enter the Wnt signaling network
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“Here, we demonstrate that the Frizzled (Fz) family of Wnt receptor”
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“Sequences of the primers for Xbra, Xnr3, and Xotx2 were as described in Yamamoto et al. (2001) and those for chordin, goosecoid, siamois, and ODC were as described in Dr. De Robertis’ home page (http://www.hhmi.ucla.edu/derobertis/ index.html).”
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“Wnt11/Fz7 can also signal through PKC to promote tissue separation behavior (Winklbauer et al. 2001), and therefore, Sfrp5 might increase adhesion between the surface cells and the deep endoderm as the blastocoel closes.”
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Unterseher, F., Hefele, J. A., Giehl, K., Robertis, E. M. D., Wedlich, D., & Schambony, A. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600332 · Cited by 153 · see citing works
“Fz 7-MO (Winklbauer et al, 2001) was used in a 500mM concentration.”
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“We note that Fz7 signaling via the Wnt/calcium pathway has been implicated in tissue movements during Xenopus gastrulation (Winklbauer et al., 2001); an analogous role in mice could explain the convergent extension defect.”
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“The following published plasmids were used to synthesize RNA for dsh-GFP (Yang-Snyder et al., 1996), dsh DIX-GFP, dsh PDZ-GFP, dsh DEP-GFP (Miller et al., 1999), dsh-myc (Sokol, 1996), fz7-myc (Winklbauer et al., 2001) and lacZ (Smith and Harland, 1991).”
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“Mesoderm explants were dissected from the lower lip region before the start of involution, as described [9].”
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DWnt4 Regulates Cell Movement and Focal Adhesion Kinase during Drosophila Ovarian Morphogenesis
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“PKC Regulates Cell Motility and FAK in Apical Cells Wnt signaling through PKC plays a role during vertebrate gastrulation (Kuhl et al., 2000; Winklbauer et al., 2001).”
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Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder
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PTK7/Otk interacts with Wnts and inhibits canonical Wnt signalling
Peradziryi, H., Kaplan, N., Podleschny, M., Liu, X., Wehner, P., Borchers, A., & Tolwinski, N. S. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.236 · Cited by 135 · see citing works
“…used for sense mRNA synthesis: PTK7–MT, DkPTK7–MT, PTK7–HA (Shnitsar and Borchers, 2008), myc-tagged Xenopus Wnt constructs (Damianitsch et al, 2009), Xwnt3a (Wolda et al, 1993), dnXwnt8 (Hoppler et al, 1996), Dsh–MT (Sokol, 1996), Fz7–MT (Winklbauer et al, 2001) and lacZ (Smith and Harland, 1991).”
MethodBen‐Shlomo, I., Hsu, S. Y., Rauch, R., Kowalski, H. W., & Hsueh, A. J. W. (2003) · Science s STKE · doi:10.1126/stke.2003.187.re9 · Cited by 135 · see citing works
Wnt11 controls cell contact persistence by local accumulation of Frizzled 7 at the plasma membrane
Witzel, S., Zimyanin, V. L., Carreira-Barbosa, F., Tada, M., & Heisenberg, C. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200606017 · Cited by 130 · see citing works
“Additionally, “knocking down” the presumed Wnt11 receptor Frizzled 7 (Fz7) in X. laevis embryos causes defects in germ layer separation at the onset of gastrulation (Winklbauer et al., 2001).”
BackgroundInfluentialWnt signaling during development of the gastrointestinal tract
Theodosiou, N. A., & Tabin, C. J. (2003) · Developmental Biology · doi:10.1016/s0012-1606(03)00185-4 · Cited by 127 · see citing works
“Wnt11, Wnt5b, and Fz7 have all been shown to signal through the planar polarity pathway (Djiane et al., 2000; Heisenberg et al., 2000; Pandur et al., 2002; Tada and Smith, 2000; Winklbauer et al., 2001).”
Das, G., Reynolds-Kenneally, J., & Mlodzik, M. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00147-8 · Cited by 125 · see citing works
Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling
Aznar, N., Midde, K., Dunkel, Y., López-Sánchez, I., Pavlova, Y., Marivin, A., Barbazán, J., Murray, F., Nitsche, U., Janssen, K., et al. (2015) · eLife · doi:10.7554/elife.07091 · Cited by 120 · see citing works
“Other Wnts, for example, Wnt5a deviate from this canonical paradigm, and trigger so-called non-canonical pathways (Kühl et al., 2000; Niehrs, 2001; Winklbauer et al., 2001).”
BackgroundXenopus paraxial protocadherin has signaling functions and is involved in tissue separation
Medina, A., Swain, R. K., Kuerner, K., & Steinbeißer, H. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600329 · Cited by 120 · see citing works
“Injection of Xfz7 alone induced separation behavior in only 30% of the explants (Winklbauer et al, 2001).”
MethodInfluentialSelf-citationGuidance of mesoderm cell migration in theXenopusgastrula requires PDGF signaling
Nagel, M., Tahinci, E., Symes, K., & Winklbauer, R. (2004) · Development · doi:10.1242/dev.01141 · Cited by 115 · see citing works
“Moreover, similar phenotypes are obtained when migration is blocked by FN antibodies (Ramos and DeSimone, 1996), or when the shear between BCR and mesoderm is mechanically alleviated by the fusion of the two layers (Winklbauer et al., 2001).”
BackgroundSelf-citationFrodo interacts with Dishevelled to transduce Wnt signals
Gloy, J., Hikasa, H., & Sokol, S. Y. (2002) · Nature Cell Biology · doi:10.1038/ncb784 · Cited by 113 · see citing works
“As a Dsh-interacting protein, Frodo may also be involved in Wnt/Dsh signalling to other targets, including the control of morphogenetic movements or cell adhesion in Xenopus embryo”
Zebrafish Gastrulation: Cell Movements, Signals, and Mechanisms
Rohde, L. A., & Heisenberg, C. (2007) · International review of cytology · doi:10.1016/s0074-7696(07)61004-3 · Cited by 107 · see citing works
Non-canonical Wnt signaling in Xenopus: regulation of axis formation and gastrulation
Kühl, M. (2002) · Seminars in Cell and Developmental Biology · doi:10.1016/s1084-9521(02)00050-2 · Cited by 108 · see citing works
Association of Dishevelled with Eph tyrosine kinase receptor and ephrin mediates cell repulsion
Tanaka, M., Kamo, T., Ota, S., & Sugimura, H. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg088 · Cited by 108 · see citing works
Lin, F. H., Sepich, D. S., Chen, S., Topczewski, J., Yin, C., Solnica‐Krezel, L., & Hamm, H. E. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200501104 · Cited by 107 · see citing works
“…A ugust 16, 2017 jcb.rupress.org D ow nloaded from http://doi.org/10.1083/jcb.200501104 Supplemental material can be found at: JCB • VOLUME 169 • NUMBER 5 • 2005778 embryos, suggesting that PTX-sensitive G proteins and PKC are involved in Xenopus gastrulation movements (Winklbauer et al., 2001).”
BackgroundInfluentialZeng, H., Hoover, A. N., & Liu, A. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.01.003 · Cited by 106 · see citing works
Holmen, S. L., Salic, A. N., Diegel, C. R., Kirschner, M. W., & Williams, B. O. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204989200 · Cited by 106 · see citing works
Dishevelled mediates ephrinB1 signalling in the eye field through the planar cell polarity pathway
Lee, H., Bong, Y., Moore, K. B., Soria, K., Moody, S. A., & Daar, I. O. (2005) · Nature Cell Biology · doi:10.1038/ncb1344 · Cited by 106 · see citing works
“1 with RNA encoding Xfz7 ΔC , a mutant non-canonical Wnt receptor lacking the cytoplasmic tail that includes the Xdsh binding sit”
MethodSato, A., Khadka, D., Liu, W., Bharti, R., Runnels, L. W., Dawid, I. B., & Habas, R. (2006) · Development · doi:10.1242/dev.02590 · Cited by 102 · see citing works
“Profilin is an evolutionarily conserved actin binding protein that is involved in actin polymerization (Watanabe and Higashida, 2004; Witke, 2004).”
BackgroundResultInfluentialRACK1 is a novel interaction partner of PTK7 that is required for neural tube closure
Wehner, P., Shnitsar, I., Urlaub, H., & Borchers, A. (2011) · Development · doi:10.1242/dev.056291 · Cited by 100 · see citing works
“, 1996), DSH-myc (Sokol, 1996), FZ7-myc (Winklbauer et al., 2001), PKC1-GFP (Sivak et al.”
MethodHurson, C. J., Butler, J. S., Keating, D., Murray, D. W., Sadlier, D. M., O’Byrne, J., & Doran, P. (2007) · BMC Musculoskeletal Disorders · doi:10.1186/1471-2474-8-12 · Cited by 100 · see citing works
“During gastrulation, frizzled-7-dependent PKC signalling controls cell-sorting behaviour in the mesoderm [36].”
Conserved Requirement of Lim1 Function for Cell Movements during Gastrulation
Hukriede, N. A., Tsang, T. E., Habas, R., Khoo, P., Steiner, K. A., Weeks, D. L., Tam, P., & Dawid, I. B. (2003) · Developmental Cell · doi:10.1016/s1534-5807(02)00398-2 · Cited by 100 · see citing works
“(Wacker et al., 2000; Winklbauer et al., 2001).”
BackgroundKagermeier-Schenk, B., Wehner, D., Özhan, G., Yamamoto, H., Li, J., Kirchner, K., Hoffmann, C., Stern, P. L., Kikuchi, A., Schambony, A., et al. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.10.015 · Cited by 97 · see citing works
Vijayaragavan, K., Szabo, E., Bosse, M. M., Ramos–Mejía, V., Moon, R. T., & Bhatia, M. (2009) · Cell stem cell · doi:10.1016/j.stem.2008.12.011 · Cited by 94 · see citing works
“This was consistent with observations in the developing mouse embryo, in which unique changes in the Fzd7 expression were induced upon Wnt11 exposure and were reflective of morphogenesis (Djiane et al., 2000; Winklbauer et al., 2001).”
BackgroundResultKrens, G., & Heisenberg, C. (2011) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-385065-2.00006-2 · Cited by 91 · see citing works
Veeman, M. T., Nakatani, Y., Hendrickson, C., Ericson, V. R., Lin, C., & Smith, W. C. (2007) · Development · doi:10.1242/dev.010892 · Cited by 91 · see citing works
“Tissue separation defects have also been described in Xenopus and zebrafish embryos with perturbed non-canonical Wnt/PCP signaling (Ulrich et al., 2003; Winklbauer et al., 2001).”
BackgroundNuclear signaling from cadherin adhesion complexes
McCrea, P. D., Maher, M. T., & Gottardi, C. J. (2015) · Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2014.11.018 · Cited by 85 · see citing works
Frizzled7: A Promising Achilles’ Heel for Targeting the Wnt Receptor Complex to Treat Cancer
Phesse, T. J., Flanagan, D. J., & Vincan, E. (2016) · Cancers · doi:10.3390/cancers8050050 · Cited by 90 · see citing works
“Fzd7 has also been shown to regulate PKC, and its translocation to the cell membrane during Xenopus gastrulation, suggesting it can regulate the Ca2+ pathway [98].”
BackgroundInfluentialMechanisms of boundary formation by Eph receptor and ephrin signaling
Cayuso, J., Xu, Q., & Wilkinson, D. G. (2014) · Developmental Biology · doi:10.1016/j.ydbio.2014.11.013 · Cited by 87 · see citing works
“During this translocation, mesoderm cells come into direct contact with ectoderm cells but mixing is prevented by a mechanism involving non-canonical Wnt signaling and activation of RhoA and Rho kinase (Chung et al., 2007; Winklbauer et al., 2001).”
BackgroundBack and forth between cell fate specification and movement during vertebrate gastrulation
Heisenberg, C., & Solnica‐Krezel, L. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2008.07.011 · Cited by 86 · see citing works
“In Xenopus laevis embryos, a distinct noncanonical Wnt signaling pathway including the Wnt receptor Frizzled and the intracellular signaling mediator PKC, ensures that internalized prechordal mesoderm separates from the overlying noninvoluted tissues allowing normal anterior migration [19].”
The Wnt signaling pathways and cell adhesion
Amin, N. (2011) · Frontiers in bioscience · doi:10.2741/3957 · Cited by 87 · see citing works
The polarity‐inducing kinase Par‐1 controls Xenopus gastrulation in cooperation with 14‐3‐3 and aPKC
Kusakabe, M., & Nishida, E. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600381 · Cited by 85 · see citing works
“This phenotype is indistinguishable from that seen in the tadpoles in which gastrulation movements are specifically impaired (Sokol, 1996; Deardorff et al, 1998; Djiane et al, 2000; Tada and Smith, 2000; Winklbauer et al, 2001).”
Carreira-Barbosa, F., Kajita, M., Morel, V., Wada, H., Okamoto, H., Arias, A. M., Fujita, Y., Wilson, S. W., & Tada, M. (2008) · Development · doi:10.1242/dev.026542 · Cited by 85 · see citing works
“Early stages of zebrafish eye formation require the coordinated activity of Wnt11, Fz5, and the Wnt/betacatenin pathway.”
InfluentialPenzo‐Méndez, A., Umbhauer, M., Djiane, A., Boucaut, J., & Riou, J. (2003) · Developmental Biology · doi:10.1016/s0012-1606(03)00067-8 · Cited by 84 · see citing works
“Depletion of Xfz7 encoded by one of the two Xfz7 pseudoalleles is sufficient to cause isolated mesendodermal tissue to mix with blastocoel roof, instead of remaining separated (Winklbauer et al., 2001).”
BackgroundInfluentialZhu, L., Zhao, J., Wang, J., Hu, C., Peng, J., Luo, R., Zhou, C., Liu, J., Lin, J., Jin, Y., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005423 · Cited by 83 · see citing works
Murphy, L. L. S., & Hughes, C. C. W. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.7.3717 · Cited by 77 · see citing works
An ATF2‐based luciferase reporter to monitor non‐canonical Wnt signaling in xenopus embryos
Ohkawara, B., & Niehrs, C. (2010) · Developmental Dynamics · doi:10.1002/dvdy.22500 · Cited by 74 · see citing works
“1E, Winklbauer et al., 2001; Schambony and Wedlich, 2007) or by dominant-negative Wnt11 (Fig.”
BackgroundFrizzled7 mediates canonical Wnt signaling in neural crest induction
Abu-Elmagd, M. M., García‐Morales, C., & Wheeler, G. N. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.06.037 · Cited by 76 · see citing works
“Neither MO1 (Winklbauer et al., 2001) nor MO3 (MO1 in Sumanas and Ekker, 2001) described previously had an effect on Xfz7 in this assay (Fig.”
BackgroundMethodInfluentialOrganising cells into tissues: new roles for cell adhesion molecules in planar cell polarity
Saburi, S., & McNeill, H. (2005) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2005.08.011 · Cited by 75 · see citing works
Webb, S., & Miller, A. L. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.08.004 · Cited by 74 · see citing works
“[77] demonstrated that when the function of the zygotic Frizzled-7 was inhibited, the normal separation that occurs between the involuted anterior mesoderm and the ectoderm was blocked, but convergent extension was not affected.”
BackgroundComparative transcriptional profiling of two human embryonic stem cell lines
Rao, R., Calhoun, J. D., Qin, X., Rekaya, R., Clark, J. K., & Stice, S. (2004) · Biotechnology and Bioengineering · doi:10.1002/bit.20245 · Cited by 83 · see citing works
“For example, Fzd7 has been shown to be involved in tissue separation during gastrulation (Winklbauer et al., 2001 ).”
Background
- Authors
- Winklbauer, R., Medina, A., Swain, R. K., & Steinbeisser, H.
- Affiliations
- Max Planck Institute for Developmental Biology (DE)
- Venue
- Nature
- Published
- 2001-10
- Volume
- 413
- Issue
- 6858
- Pages
- 856-860
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1664587663
- Cited by
- 263
- References
- 21
- Citations by year
- 2026: 3 · 2025: 1 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 9 · 2015: 8 · 2014: 8 · 2013: 5 · 2012: 11
- FWCI
- 8.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Planarian Biology and Electrostimulation
- Keywords
- Frizzled-7, Wnt signaling, gastrulation, Xenopus laevis, protein kinase C, trimeric G proteins, cell sorting, mesoderm, ectoderm, planar cell polarity, convergent extension, dorsal-ventral axis, β-catenin signaling
- MeSH terms
- Animals, Cytoskeletal Proteins, Embryo, Nonmammalian, Fibroblast Growth Factors, Gastrula, Mesoderm, Morphogenesis, Protein Kinase C, Receptors, Cell Surface, Xenopus laevis, Signal Transduction, Trans-Activators, Gene Expression, Oligonucleotides, Antisense, Cell Polarity, GTP-Binding Proteins, Xenopus Proteins, Receptors, G-Protein-Coupled, beta Catenin
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