Neural inhibition by c-Jun as a synergizing factor in bone morphogenetic protein 4 signaling.
The transcription factor, activator protein 1 (AP-1) complexes (c-Jun and c-Fos heterodimers) has been shown to interact with transforming growth factor beta signaling in mammalian cells and Drosophila embryo. Here we show that c-Jun alone is involved in the anti-neuralizing activity of bone morphogenetic protein 4, a transforming growth factor beta superfamily member, in Xenopus neurogenesis. Co-injection of mRNAs encoding c-jun and a dominant negative bone morphogenetic protein receptor completely inhibits dominant negative bone morphogenetic protein receptor-induced neuralization and reverses the epidermal fate in the animal cap. Surprisingly, a dominant negative c-Jun does not induce neural tissue in the animal cap, but it synergizes with dominant negative bone morphogenetic protein receptor for neural induction. Temporal analysis using a dexamethasone-inducible c-Jun shows that exogenous c-Jun activity must be turned on before or at stage 11 to fulfill the anti-neuralizing effect. Neural inhibition by c-Jun does not occur until stage 13 suggesting that c-Jun probably acts by suppressing neural maintenance rather than neural initiation. This is also supported by the fact that c-Jun does not inhibit expression of the neural-initializing gene Zic-r1 but the neural cofactor Sox2, and that ectopic expression of Sox2 attenuates the anti-neuralizing effect of c-Jun. Finally, we display that the c-Jun effect is enhanced by an auto-regulatory loop between c-Jun and bone morphogenetic protein. These studies suggest that c-Jun/AP-1 is a converging point in both the fibroblast growth factor and transforming growth factor beta signaling pathways. Based on our findings, we propose that c-Jun synergizes with bone morphogenetic protein 4 signaling to inhibit neural development in Xenopus ectoderm.
Peng
Y
Y
Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, NCI-FCRDC, National Institutes of Health, Frederick, MD 21702-1201, USA.
Xu
R-H
RH
Mei
J-M
JM
Li
X-P
XP
Yan
D
D
Kung
H-F
HF
Phang
J M
JM
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D004627:Embryonic Induction / Q000235:genetics*; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D024002:HMGB Proteins; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D009433:Neural Inhibition / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics; D017978:Receptors, Growth Factor; D055748:SOXB1 Transcription Factors; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics; D014157:Transcription Factors; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology* / Q000235:genetics / Q000378:metabolism
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D024002:HMGB Proteins; D019006:Neural Cell Adhesion Molecules; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D055748:SOXB1 Transcription Factors; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D029867:Xenopus Proteins; C525812:bmp4 protein, Xenopus; C527781:sox2 protein, Xenopus; D052004:Bone Morphogenetic Protein Receptors