0 Patent citations 5 Scholarly citations Reference Count: 31
Ying Peng;Ren-He Xu;Jay M Mei;Xiaohui Li;D Yan;Hsiang-Fu Kung;James M Phang
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 β 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 β 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 β 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.
National Institutes of Health;Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, NCI-FCRDC, National Institutes of Health, Frederick, MD 21702-1201, USA.WiCellNational Institutes of HealthSofia Medical UniversityBar-Ilan UniversityUniversity of Hong KongNational Institutes of Health