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When Wnts antagonize Wnts.

Weidinger G, Moon RT - J. Cell Biol. (2003)

Bottom Line: Secreted Wnt ligands appear to activate a variety of signaling pathways.Two papers in this issue now present genetic evidence that "noncanonical" Wnt signaling inhibits the "canonical" Wnt/beta-catenin pathway.These studies present the first genetic confirmation of the previous hypothesis that vertebrate Wnt signaling pathways can act in an antagonistic manner.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Box 357370, Seattle, WA 98195, USA.

ABSTRACT
Secreted Wnt ligands appear to activate a variety of signaling pathways. Two papers in this issue now present genetic evidence that "noncanonical" Wnt signaling inhibits the "canonical" Wnt/beta-catenin pathway. Westfall et al. (2003a) show that zebrafish embryos lacking maternal Wnt-5 function are dorsalized due to ectopic activation of beta-catenin, whereas Topol et al. (2003) report that chondrogenesis in the distal mouse limb bud depends on inhibition of Wnt/beta-catenin signaling by a paralogue of Wnt-5. These studies present the first genetic confirmation of the previous hypothesis that vertebrate Wnt signaling pathways can act in an antagonistic manner.

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Vertebrate Wnt-5 paralogues antagonize Wnt/β-catenin signaling. (A) A highly schematized model of antagonistic interactions of maternal Wnt signaling pathways in early Xenopus or zebrafish embryos. In response to Dishevelled (Dsh) and perhaps a Wnt signal, high β-catenin levels specify the dorsal side. Maternal Wnt-5 is required for development of ventral cell fates by antagonizing β-catenin signaling, although where Wnt-5 is active remains unclear. (B) A simplistic model of Wnt antagonism in the mouse limb bud. The limb ectoderm and apical ectodermal ridge (AER) meet at the distal limb bud. As several Wnts (e.g., Wnt7a or Wnt3) that are able to activate canonical Wnt/β-catenin signaling are expressed in the limb ectoderm and apical ectodermal ridge, the distal limb bud has a higher level of canonical Wnt/β-catenin signaling, which suppresses chondrogenesis. In the distal limb bud, Wnt-5a signaling decreases β-catenin levels, which allows chondrogenesis to occur.
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fig1: Vertebrate Wnt-5 paralogues antagonize Wnt/β-catenin signaling. (A) A highly schematized model of antagonistic interactions of maternal Wnt signaling pathways in early Xenopus or zebrafish embryos. In response to Dishevelled (Dsh) and perhaps a Wnt signal, high β-catenin levels specify the dorsal side. Maternal Wnt-5 is required for development of ventral cell fates by antagonizing β-catenin signaling, although where Wnt-5 is active remains unclear. (B) A simplistic model of Wnt antagonism in the mouse limb bud. The limb ectoderm and apical ectodermal ridge (AER) meet at the distal limb bud. As several Wnts (e.g., Wnt7a or Wnt3) that are able to activate canonical Wnt/β-catenin signaling are expressed in the limb ectoderm and apical ectodermal ridge, the distal limb bud has a higher level of canonical Wnt/β-catenin signaling, which suppresses chondrogenesis. In the distal limb bud, Wnt-5a signaling decreases β-catenin levels, which allows chondrogenesis to occur.

Mentions: The laboratories of Diane Slusarski and Yingzi Yang now present this genetic evidence (Fig. 1) (Westfall et al., 2003a; Topol et al., 2003). Slusarski's laboratory shows that removal of both the maternal and zygotic function of zebrafish Wnt-5 (MZWnt-5) not only enhances the morphogenesis defects of zygotic Wnt-5 mutants, but also results in variable degrees of dorsalization, including formation of a secondary axis (Westfall et al., 2003a). These phenotypes resemble those obtained by overactivation of Wnt/β-catenin signaling, and indeed the authors find ectopic stabilization of β-catenin and ectopic expression of β-catenin target genes in MZWnt-5 mutant embryos. These findings add strong genetic support to the previously suggested requirement of a Wnt signal for development of ventral cell fates and antagonism of dorsal fates, as has been proposed based on the ability of dominant–negative forms of Wnt-11 and of a frizzled receptor to interfere with ventral cell fates in Xenopus (Itoh and Sokol, 1999; Kühl et al., 2000a). Similarly, Yang's laboratory shows that in the distal tip of mouse limb buds Wnt-5a antagonizes Wnt/β-catenin signaling, since in Wnt-5a−/− limbs higher levels of β-catenin can be detected in the distal tip where a β-catenin–responsive reporter is ectopically expressed (Topol et al., 2003). Chondrocyte differentiation, which is defective in the Wnt-5a−/− limbs, can be partially restored by transplantation of cells expressing a secreted Wnt inhibitor, which presumably interferes with canonical Wnts only. Thus, in the mouse limb bud, Wnt-5a signaling appears to promote chondrocyte differentiation by antagonizing the Wnt/β-catenin pathway.


When Wnts antagonize Wnts.

Weidinger G, Moon RT - J. Cell Biol. (2003)

Vertebrate Wnt-5 paralogues antagonize Wnt/β-catenin signaling. (A) A highly schematized model of antagonistic interactions of maternal Wnt signaling pathways in early Xenopus or zebrafish embryos. In response to Dishevelled (Dsh) and perhaps a Wnt signal, high β-catenin levels specify the dorsal side. Maternal Wnt-5 is required for development of ventral cell fates by antagonizing β-catenin signaling, although where Wnt-5 is active remains unclear. (B) A simplistic model of Wnt antagonism in the mouse limb bud. The limb ectoderm and apical ectodermal ridge (AER) meet at the distal limb bud. As several Wnts (e.g., Wnt7a or Wnt3) that are able to activate canonical Wnt/β-catenin signaling are expressed in the limb ectoderm and apical ectodermal ridge, the distal limb bud has a higher level of canonical Wnt/β-catenin signaling, which suppresses chondrogenesis. In the distal limb bud, Wnt-5a signaling decreases β-catenin levels, which allows chondrogenesis to occur.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172824&req=5

fig1: Vertebrate Wnt-5 paralogues antagonize Wnt/β-catenin signaling. (A) A highly schematized model of antagonistic interactions of maternal Wnt signaling pathways in early Xenopus or zebrafish embryos. In response to Dishevelled (Dsh) and perhaps a Wnt signal, high β-catenin levels specify the dorsal side. Maternal Wnt-5 is required for development of ventral cell fates by antagonizing β-catenin signaling, although where Wnt-5 is active remains unclear. (B) A simplistic model of Wnt antagonism in the mouse limb bud. The limb ectoderm and apical ectodermal ridge (AER) meet at the distal limb bud. As several Wnts (e.g., Wnt7a or Wnt3) that are able to activate canonical Wnt/β-catenin signaling are expressed in the limb ectoderm and apical ectodermal ridge, the distal limb bud has a higher level of canonical Wnt/β-catenin signaling, which suppresses chondrogenesis. In the distal limb bud, Wnt-5a signaling decreases β-catenin levels, which allows chondrogenesis to occur.
Mentions: The laboratories of Diane Slusarski and Yingzi Yang now present this genetic evidence (Fig. 1) (Westfall et al., 2003a; Topol et al., 2003). Slusarski's laboratory shows that removal of both the maternal and zygotic function of zebrafish Wnt-5 (MZWnt-5) not only enhances the morphogenesis defects of zygotic Wnt-5 mutants, but also results in variable degrees of dorsalization, including formation of a secondary axis (Westfall et al., 2003a). These phenotypes resemble those obtained by overactivation of Wnt/β-catenin signaling, and indeed the authors find ectopic stabilization of β-catenin and ectopic expression of β-catenin target genes in MZWnt-5 mutant embryos. These findings add strong genetic support to the previously suggested requirement of a Wnt signal for development of ventral cell fates and antagonism of dorsal fates, as has been proposed based on the ability of dominant–negative forms of Wnt-11 and of a frizzled receptor to interfere with ventral cell fates in Xenopus (Itoh and Sokol, 1999; Kühl et al., 2000a). Similarly, Yang's laboratory shows that in the distal tip of mouse limb buds Wnt-5a antagonizes Wnt/β-catenin signaling, since in Wnt-5a−/− limbs higher levels of β-catenin can be detected in the distal tip where a β-catenin–responsive reporter is ectopically expressed (Topol et al., 2003). Chondrocyte differentiation, which is defective in the Wnt-5a−/− limbs, can be partially restored by transplantation of cells expressing a secreted Wnt inhibitor, which presumably interferes with canonical Wnts only. Thus, in the mouse limb bud, Wnt-5a signaling appears to promote chondrocyte differentiation by antagonizing the Wnt/β-catenin pathway.

Bottom Line: Secreted Wnt ligands appear to activate a variety of signaling pathways.Two papers in this issue now present genetic evidence that "noncanonical" Wnt signaling inhibits the "canonical" Wnt/beta-catenin pathway.These studies present the first genetic confirmation of the previous hypothesis that vertebrate Wnt signaling pathways can act in an antagonistic manner.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Box 357370, Seattle, WA 98195, USA.

ABSTRACT
Secreted Wnt ligands appear to activate a variety of signaling pathways. Two papers in this issue now present genetic evidence that "noncanonical" Wnt signaling inhibits the "canonical" Wnt/beta-catenin pathway. Westfall et al. (2003a) show that zebrafish embryos lacking maternal Wnt-5 function are dorsalized due to ectopic activation of beta-catenin, whereas Topol et al. (2003) report that chondrogenesis in the distal mouse limb bud depends on inhibition of Wnt/beta-catenin signaling by a paralogue of Wnt-5. These studies present the first genetic confirmation of the previous hypothesis that vertebrate Wnt signaling pathways can act in an antagonistic manner.

Show MeSH
Related in: MedlinePlus