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Mutual antagonism between dickkopf1 and dickkopf2 regulates Wnt/beta-catenin signalling
1Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Abstract:
Wnts are secreted glycoproteins implicated in diverse processes during embryonic patterning in metazoans. They signal through seven-transmembrane receptors of the Frizzled (Fz) family [1] to stabilise beta-catenin [2]. Wnts are antagonised by several extracellular inhibitors including the product of the dickkopf1 (dkk1) gene, which was identified in Xenopus embryos and is a member of a multigene family. The dkk1 gene acts upstream of the Wnt pathway component dishevelled but its mechanism of action is unknown [3]. Although the function of Dkk1 as a Wnt inhibitor in vertebrates is well established [3-6], the effect of other Dkks on the Wnt/beta-catenin pathway is unclear. Here, we report that a related family member, Dkk2, activates rather than inhibits the Wnt/beta-catenin signalling pathway in Xenopus embryos. Dkk2 strongly synergised with Wnt receptors of the Fz family to induce Wnt signalling responses. The study identifies Dkk2 as a secreted molecule that is able to activate Wnt/beta-catenin signalling. The results suggest that a coordinated interplay between inhibiting dkk1 and activating dkk2 can modulate Fz signalling.
Insights
Dickkopf-2 (Dkk2) activates Wnt/beta-catenin signaling in Xenopus embryos, unlike its inhibitor counterpart, Dickkopf-1 (Dkk1). This discovery reveals Dkk2
Area of Science:
- Developmental biology
- Molecular signaling
Background:
- Wnt proteins are crucial for embryonic patterning, signaling via Frizzled (Fz) receptors to stabilize beta-catenin.
- Dickkopf-1 (Dkk1) is a known antagonist of the Wnt pathway, acting upstream of dishevelled.
- The specific roles of other Dickkopf (Dkk) family members in Wnt signaling remain largely uncharacterized.
Purpose of the Study:
- To investigate the function of Dickkopf-2 (Dkk2) in the Wnt/beta-catenin signaling pathway.
- To determine whether Dkk2 acts as an inhibitor or activator of Wnt signaling in embryonic development.
Main Methods:
- Utilized Xenopus embryos as a model system.
- Examined the effects of Dkk2 on Wnt/beta-catenin signaling responses.
- Assessed the synergy between Dkk2 and Frizzled (Fz) receptors.
Main Results:
- Dickkopf-2 (Dkk2) was found to activate, not inhibit, the Wnt/beta-catenin signaling pathway in Xenopus embryos.
- Dkk2 demonstrated strong synergy with Frizzled (Fz) family receptors, enhancing Wnt signaling.
- Identified Dkk2 as a secreted molecule capable of activating Wnt/beta-catenin signaling.
Conclusions:
- Dkk2 functions as an activator of Wnt/beta-catenin signaling in vertebrate embryos.
- The interplay between Dkk1 (inhibitor) and Dkk2 (activator) provides a mechanism for modulating Frizzled (Fz) signaling during development.