Editors' ChoiceWnt signaling

Two Inhibitors in One

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Sci. Signal.  02 Dec 2008:
Vol. 1, Issue 48, pp. ec416
DOI: 10.1126/scisignal.148ec416

Dickkopf-1 (Dkk1), which inhibits canonical Wnt/β-catenin signaling by binding to the Wnt coreceptors LDL-related protein 5 (LRP5) and LRP6 through its carboxy-terminal cysteine-rich domain (C1), induces heart and head cell fates in Xenopus laevis embryos more potently than do other Wnt antagonists, suggesting that it may have additional roles. Korol et al. report that the amino-terminal cysteine-rich domain (N1) of Dkk1 is required for its maximal induction of cell fate and functions independently of canonical Wnt signaling. Overexpression of Dkk1 alone induces ectopic cement gland, the most anterior structure in the embryo, and heart tissues in embryos, and co-overexpression of Dkk1 with a truncated receptor that inhibits bone morphogenetic protein signaling induces the formation of a secondary body axis. When tested in these overexpression assays, the N1 domain did not induce ectopic tissues, the C1 domain induced some ectopic tissues, and N1 + C1 induced more ectopic tissues than C1 alone but less than did full-length Dkk1. Overexpressing N1 plus either of the Wnt antagonists Crescent or Wnt inhibitory factor 1 (WIF-1) mimicked the heart-inducing ability of N1 plus C1 but failed to drive morphogenesis of the ectopic hearts as well as did overexpression of full-length Dkk1. Coexpression of N1 with Crescent or WIF-1 enhanced the ability of the latter to induce ectopic cement glands and hearts. Combining the activities of the N1 and C1 domains made Dkk1 a more powerful inducer of cell fates than were proteins that simply inhibit canonical Wnt signaling. N1 did not affect expression of genes regulated by canonical Wnt or Nodal signaling pathways in animal cap assays, so the authors speculate that the N1 domain could play a role in inhibiting noncanonical Wnt signaling through the Frizzled receptors.

O. Korol, R. W. Gupta, M. Mercola, A novel activity of the Dickkopf-1 amino terminal domain promotes axial and heart development independently of canonical Wnt inhibition. Dev Biol. 324, 131–138 (2008). [PubMed]