近日,，國際重要學術(shù)期刊《美國科學院院刊》（PNAS）發(fā)表了上海生科院生化與細胞所景乃禾研究組的最新研究成果,，揭示了視黃酸（RA）調(diào)控BMP信號通路活性的分子機制,，及其在神經(jīng)管發(fā)育過程中的調(diào)節(jié)作用,。這項工作主要由博士研究生盛能印等在景乃禾研究員的指導下完成。
BMP信號是調(diào)控胚胎發(fā)育的重要信號通路之一,，該信號途徑的異常會導致胚胎發(fā)育的紊亂或癌癥的發(fā)生,，因此對BMP信號的調(diào)節(jié)具有重要的生物學意義。已有的研究表明,，形態(tài)生成素FGF和Wnt都可以調(diào)節(jié)BMP信號活性,，并且這種不同信號通路間的整合對早期胚胎的體軸形成非常重要。在中樞神經(jīng)系統(tǒng)的發(fā)育過程中,，BMP信號也發(fā)揮重要作用，但在此過程中BMP通路是否也與其他信號途徑發(fā)生整合并不清楚,。
景乃禾研究組盛能印博士等發(fā)現(xiàn),，RA通過其核內(nèi)受體RAR上調(diào)Gadd45家族成員的表達，而Gadd45隨后活化MAPK通路,，進而促進磷酸化Smad1與其E3泛素化連接酶的結(jié)合,，導致磷酸化的Smad1蛋白降解，抑制BMP信號通路的活性,。進一步的研究發(fā)現(xiàn),，RA通過相似的分子機制在雞胚神經(jīng)管內(nèi)調(diào)控BMP信號途徑的活性，以此調(diào)節(jié)雞胚神經(jīng)管背腹軸的模式形成,。
該研究首次發(fā)現(xiàn)了RA與BMP信號通路之間的調(diào)控機制,，并揭示了這兩條重要信號途徑間整合的生物學意義，增強了人們對胚胎發(fā)育過程中,，各種形態(tài)生成素之間相互整合以調(diào)節(jié)胚胎模式化進程的理解,。
該項工作得到了國家科技部、國家自然科學基金委,、中國科學院以及上海市科委的經(jīng)費支持,。（生物谷Bioon.com）
生物谷推薦英文摘要：
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.
