The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death.
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.
Grotewold
Lars
L
Entwicklungs- und Molekularbiologie der Tiere, Heinrich-Heine Universität, D-40225 Düsseldorf, Germany. lars.grotewold@uni-duesseldorf.de
Rüther
Ulrich
U
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D002352:Carrier Proteins; D002642:Chick Embryo; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004343:Drug Implants; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005121:Extremities / Q000196:embryology*; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014466:Ultraviolet Rays; D014921:Wings, Animal / Q000196:embryology*; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D004343:Drug Implants; D004791:Enzyme Inhibitors; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D019311:Staurosporine; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C495267:CTNNB1 protein, mouse; C501127:Dkk1 protein, mouse; C496457:Fgf8 protein, mouse; C525813:bmp4 protein, zebrafish; C501128:dkk1b protein, zebrafish