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Neural inhibition by c-Jun as a synergizing factor in bone morphogenetic protein 4 signaling
1Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, NCI-FCRDC, National Institutes of Health, Frederick, MD 21702-1201, USA.
Abstract:
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.
Insights
Activator protein 1 (AP-1) transcription factor c-Jun inhibits Xenopus neurogenesis by suppressing neural maintenance, working with bone morphogenetic protein 4 signaling to block neural development.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cell Signaling
Background:
- The transcription factor activator protein 1 (AP-1) complexes, including c-Jun and c-Fos heterodimers, are known to interact with transforming growth factor beta (TGF-β) signaling.
- Previous studies have indicated interactions between AP-1 and TGF-β signaling in mammalian cells and Drosophila embryos.
- Bone morphogenetic protein 4 (BMP4), a member of the TGF-β superfamily, plays a role in embryonic development.
Purpose of the Study:
- To investigate the role of c-Jun alone in the anti-neuralizing activity of BMP4 during Xenopus neurogenesis.
- To elucidate the mechanism by which c-Jun influences neural development in Xenopus ectoderm.
- To determine the relationship between c-Jun, BMP4 signaling, and neural fate determination.
Main Methods:
- mRNA injection of c-jun and dominant-negative BMP receptor in Xenopus embryos.
- Temporal analysis using a dexamethasone-inducible c-Jun system.
- Analysis of neural-initializing and neural cofactor gene expression (Zic-r1, Sox2).
- Investigation of auto-regulatory loops between c-Jun and BMP signaling.
Main Results:
- Co-injection of c-jun and dominant-negative BMP receptor mRNA inhibited BMP receptor-induced neuralization and reversed epidermal fate.
- Dominant-negative c-Jun alone did not induce neural tissue but synergized with dominant-negative BMP receptor for neural induction.
- Exogenous c-Jun activity required activation before or at stage 11 for anti-neuralizing effects, while inhibition occurred at stage 13, suggesting neural maintenance suppression.
- c-Jun inhibited Sox2 expression but not Zic-r1; ectopic Sox2 expression attenuated c-Jun's anti-neuralizing effect.
- The effect of c-Jun was enhanced by an auto-regulatory loop with BMP signaling.
Conclusions:
- c-Jun acts as an anti-neuralizing factor in Xenopus neurogenesis, likely by suppressing neural maintenance rather than initiation.
- c-Jun and BMP4 signaling synergize to inhibit neural development in Xenopus ectoderm.
- c-Jun/AP-1 represents a converging point for fibroblast growth factor and TGF-β signaling pathways in neural development.