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The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death
Lars Grotewold1, Ulrich Rüther
1Entwicklungs- und Molekularbiologie der Tiere, Heinrich-Heine Universität, D-40225 Düsseldorf, Germany. lars.grotewold@uni-duesseldorf.de
Abstract:
Dickkopf-1 (Dkk-1) has been shown to be a potent inhibitor of Wnt/beta-catenin signaling in a variety of assays and organisms. In this study, we show that expression of Dkk-1 overlaps significantly 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/beta-catenin signaling in response to different stress signals that all converge on the activation of c-Jun in vivo.
Insights
Dickkopf-1 (Dkk-1) inhibits Wnt/beta-catenin signaling and is upregulated by stress. Its expression is linked to programmed cell death in vertebrate limb development, regulated by Bmp-4 and c-Jun.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cell Death Research
Background:
- Dickkopf-1 (Dkk-1) is a known inhibitor of the Wnt/beta-catenin signaling pathway.
- Wnt/beta-catenin signaling plays crucial roles in embryonic development and tissue homeostasis.
- Understanding Dkk-1 regulation is vital for comprehending developmental processes and cellular responses to stress.
Purpose of the Study:
- To investigate the role and regulation of Dickkopf-1 (Dkk-1) during vertebrate limb development.
- To identify upstream regulators of Dkk-1 expression, particularly in response to stress.
- To elucidate the connection between Dkk-1, programmed cell death, and Wnt/beta-catenin signaling.
Main Methods:
- Analysis of Dkk-1 expression patterns in normal and mutant vertebrate limb development.
- Identification and validation of upstream regulators of Dkk-1, including Bmp-4 and c-Jun.
- Investigation of Dkk-1 regulation by genotoxic stimuli such as UV irradiation.
- Assessment of Dkk-1's effect on Bmp-induced apoptosis in vertebrate limbs.
Main Results:
- Dkk-1 expression significantly overlaps with sites of programmed cell death in vertebrate limb development.
- Bmp-4 was identified as an upstream regulator, activating Dkk-1 specifically when inducing apoptosis.
- Dkk-1 expression is upregulated by UV irradiation and other genotoxic stresses.
- Normal Dkk-1 expression is dependent on the Ap-1 family member c-Jun.
- Overexpression of Dkk-1 potentiates Bmp-triggered apoptosis in the vertebrate limb.
Conclusions:
- Dkk-1 plays a significant role in programmed cell death during vertebrate limb development.
- Stress signals, converging on c-Jun activation, lead to Dkk-1 upregulation.
- Dkk-1-mediated inhibition of Wnt/beta-catenin signaling is a key response to various stress signals in vivo.