Further Development 11.9: Frzb, Dickkopf, Notum, and Tiki: More Ways to Block Wnts

Amphibians and Fish

Shortly after the attributes of Cerberus were demonstrated, two other proteins, Frzb and Dickkopf, were found to be synthesized in the involuting endomesoderm. Frzb (pronounced “frisbee”) is a small, soluble form of Frizzled (the Wnt receptor) that is capable of binding Wnt proteins in solution (Figure 1A, B; Leyns et al. 1997; Wang et al. 1997). Frzb is synthesized predominantly in the endomesoderm cells beneath the prospective brain (Figure 1C). If embryos are made to synthesize excess Frzb, Wnt signaling fails to occur throughout the embryo; such embryos lack ventral posterior structures and become “all head (Figure 1D).” The Dickkopf (German, “thick head,” “stubborn”) protein also appears to interact directly with the Wnt receptors, preventing Wnt signaling (Mao et al. 2001, 2002). Injection of antibodies against Dickkopf causes the resulting embryos to have small, deformed heads with no forebrain (Glinka et al. 1998).

Figure 1 Inhibiting Wnt signaling enables head formation. (A) Frzb protein is secreted by the anterior region of the organizer. It must bind to Xwnt8 before that inducer can bind to its receptor. Frzb resembles the Wnt-binding domain of the Wnt receptor (the Frizzled protein), but Frzb is a soluble molecule. (B) Xwnt8 is made throughout the marginal zone. (C) Double in situ hybridization localizing Frzb (dark stain) and Chordin (reddish stain) messages. The frzb mRNA is transcribed in the head endomesoderm of the organizer, but not in the notochord (where chordin is expressed). (D) Injecting cerberus mRNA into a single D4 (ventral vegetal) blastomere of a 32-cell Xenopus embryo induces head structures as well as a duplicated heart and liver. The secondary eye (a single cyclopic eye) and olfactory placode can be readily seen. Xwnt8 is capable of ventralizing the mesoderm and of preventing anterior head formation in the ectoderm.

Two other organizer proteins, Tiki and Notum, have recently been found to bind to Wnt proteins during gastrulation. Tiki not only prevents Wnts from binding to their receptors, it cleaves the Wnt to render it nonfunctional. Tiki is synthesized primarily in the anterior regions of the organizer and is crucial for head formation in Xenopus (Zhang et al. 2012.) And to make certain that Wnt doesn’t stop brain development, the ectoderm itself makes a membrane-tethered Wnt inhibitor, Notum, that acts by removing the lipid moiety that keeps the Wnt proteins from forming inactive dimers with one another (Zhang et al. 2015).

Literature Cited

Glinka, A., W. Wu, A. P. Monaghan, C. Blumenstock and C. Niehrs. 1998. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 391: 357–362.

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Leyns, L., T. Bouwmeester, S.-H. Kim, S. Piccolo and E. M. De Robertis. 1997. Frzb-1 is a secreted antagonist of Wnt signaling expressed in the Spemann organizer. Cell 88: 747–756.

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Wang, S., M. Krinks, K. Lin, F. P. Luyten and M. Moos, Jr. 1997. Frzb, a secreted protein expressed in the Spemann organizer, binds and inhibits Wnt-8. Cell 88: 757–766.

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Zhang, X. and 11 others. 2012. Tiki1 is required for head formation via Wnt cleavage-oxidation and inactivation. Cell 149: 1565–1577.

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Zhang, X., and 8 others. 2015. Notum is required for neural and head induction via Wnt deacylation, oxidation, and inactivation. Dev Cell 32: 719–730.

Mao, B. and 11 others. 2002. Kremen proteins are Dickkopf receptors that regulate Wnt/b-catenin signalling. Nature 417: 664–667.

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Mao, B., W. Wu, D. Hoppe, P. Stannek, A. Glinka and C. Niehrs. 2001. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411: 321–325.

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