近日，国际重要学术期刊《美国科学院院刊》（PNAS）发表了上海生科院生化与细胞所景乃禾研究组的最新研究成果，揭示了视黄酸（RA）调控BMP信号通路活性的分子机制，及其在神经管发育过程中的调节作用。这项工作主要由博士研究生盛能印等在景乃禾研究员的指导下完成。
BMP信号是调控胚胎发育的重要信号通路之一，该信号途径的异常会导致胚胎发育的紊乱或癌症的发生，因此对BMP信号的调节具有重要的生物学意义。已有的研究表明，形态生成素FGF和Wnt都可以调节BMP信号活性，并且这种不同信号通路间的整合对早期胚胎的体轴形成非常重要。在中枢神经系统的发育过程中，BMP信号也发挥重要作用，但在此过程中BMP通路是否也与其他信号途径发生整合并不清楚。
景乃禾研究组盛能印博士等发现，RA通过其核内受体RAR上调Gadd45家族成员的表达，而Gadd45随后活化MAPK通路，进而促进磷酸化Smad1与其E3泛素化连接酶的结合，导致磷酸化的Smad1蛋白降解，抑制BMP信号通路的活性。进一步的研究发现，RA通过相似的分子机制在鸡胚神经管内调控BMP信号途径的活性，以此调节鸡胚神经管背腹轴的模式形成。
该研究首次发现了RA与BMP信号通路之间的调控机制，并揭示了这两条重要信号途径间整合的生物学意义，增强了人们对胚胎发育过程中，各种形态生成素之间相互整合以调节胚胎模式化进程的理解。
该项工作得到了国家科技部、国家自然科学基金委、中国科学院以及上海市科委的经费支持。（生物谷Bioon.com）
生物谷推荐英文摘要：
PNAS doi: 10.1073/pnas.1009244107
Retinoic acid regulates bone morphogenic protein signal duration by promoting the degradation of phosphorylated Smad1
Nengyin Shenga, Zhihui Xiea, Chen Wanga, Ge Baia, Kejing Zhanga, Qingqing Zhua, Jianguo Songa, Francois Guillemotb, Ye-Guang Chenc, Anning Lina,d, and Naihe Jinga,1
The proper function of the bone morphogenic protein (BMP) pathway during embryonic development and organ maintenance requires its communication with other signaling pathways. Unlike the well-documented regulation of the BMP pathway by FGF/MAPK and Wnt/GSK3 signals, cross-talk between BMP/Smad and retinoic acid (RA)/RA receptor (RAR) pathways is poorly understood. Here, we show that RA represses BMP signal duration by reducing the level of phosphorylated Smad1 (pSmad1). Through its nuclear receptor-mediated transcription, RA enhances the interaction between pSmad1 and its ubiquitin E3 ligases, thereby promoting pSmad1 ubiquitination and proteasomal degradation. This regulation depends on the RA-increased Gadd45 expression and MAPK activation. During the neural development in chicken embryo, the RA/RAR pathway also suppresses BMP signaling to antagonize BMP-regulated proliferation and differentiation of neural progenitor cells. Furthermore, this cross-talk between RA and BMP pathways is involved in the proper patterning of dorsal neural tube of chicken embryo. Our results reveal a mechanism by which RA suppresses BMP signaling through regulation of pSmad1 stability.
