The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death

Abstract

Dickkopf-1 (Dkk-1) has been shown to be a potent inhibitor of Wnt/b-catenin signaling in a variety of assays and organisms. In this study, we show that expression of Dkk-1 overlaps signi®cantly with the sites of programmed cell death in normal as well as mutant vertebrate limb development, and identify several of its upstream regulators, one of which is Bmp-4. Interestingly, Bmp-4 only activates Dkk-1 when it concomitantly induces apoptosis. Moreover, Dkk-1 is heavily up-regulated by UV irradiation and several other genotoxic stimuli. We further show that normal expression of Dkk-1 is dependent on the Ap-1 family member c-Jun and that overexpression of Dkk-1 enhances Bmp-triggered apoptosis in the vertebrate limb. Taken together, our results provide evidence for an important role of Dkk-1-mediated inhibition of Wnt/b-catenin signaling in response to different stress signals that all converge on the activation of c-Jun in vivo.

Function and biological roles of the Dickkopf family of Wnt modulators

“…Hence, induction of Dkk1 may be involved in an apoptosis pathway. This is supported by the observation that Dkk1 is a transcriptional target of p53 and is proapoptotic in limb development (Grotewold and Ru¨ther, 2002), in mesothelioma (Lee et al, 2004), as well as in human glioma cells, where it is induced by DNA damage (Shou et al, 2002).…”

“…An expansion of the AER is observed in both Dkk1 null and hypomorphic Dkk1 d/d mutants, suggesting a genetic interaction with Wnt3 (Mukhopadhyay et al, 2001;Adamska et al, 2004;MacDonald et al, 2004). In the control of the AER, Wnt3 lies upstream of BMP ligands (Barrow et al, 2003) and Dkk1 interacts with BMPs in this context, as they can mutually induce each others expression (Mukhopadhyay et al, 2001;Grotewold and Ru¨ther, 2002).…”

“…During early limb development, Wnt/b-catenin signaling by Wnt3 is required for formation of the apical ectodermal ridge (AER), since Wnt3 mutants have a reduced AER (Barrow et al, 2003;Soshnikova et al, 2003), a signaling center that dictates limb growth. Similarly, overexpression of Dkk1 in chicks induces limb truncation and this is accompanied by apoptosis (Mukhopadhyay et al, 2001;Grotewold and Ru¨ther, 2002). Conversely, overactivation of Wnt signaling by expression of a gain-of-function mutation of b-catenin results in expansion of the AER (Soshnikova et al, 2003).…”

Thalidomide Resistance Is Based on the Capacity of the Glutathione-Dependent Antioxidant Defense

“…Hydrogen peroxide, in turn, has been shown to induce Dkk1 expression in MEFs. 12,13 However, thalidomide potentiated DEMinduced Dkk1 expression ( Figure 5A). Importantly, thalidomide-induced apoptosis in DEM-pretreated MEFs was reduced by PBN or MnTBAP as well as by Noggin, Dkk1 blocking antibodies (RDkk1), bpV(pic) or BIO ( Figure 5B,C).…”

Anteroposterior patterning in the limb and digit specification: Contribution of mouse genetics

“…It has been shown that anterior limb mesenchyme is the place for prominent cell death at E11.5 (Grotewold and Ruther, 2002a;our personal data). This finding may be Dickkopf-dependent, as Dkk1 is a BMP target gene (Mukhopadhyay et al, 2001;Grotewold and Ruther, 2002b). At this stage, the Xt/Xt homozygote limb displays an anterior overgrowth that will lead to polydactyly, suggesting that in the absence of Gli3R, cell death is abolished.…”