近日來自中國科學(xué)院上海生命科學(xué)研究院生物化學(xué)與細(xì)胞生物學(xué)研究所的研究人員在新研究中揭示了Smad6調(diào)控Wnt/β-catenin信號(hào)通路的分子機(jī)制，及其在脊髓背側(cè)神經(jīng)元分化過程中的功能。相關(guān)研究論文于7月5日發(fā)表在國際重要學(xué)術(shù)期刊美國《國家科學(xué)院院刊》(PNAS)上,。
這項(xiàng)工作主要由博士研究生謝治慧,、陳永峰等在景乃禾研究員的指導(dǎo)下完成。后者早年畢業(yè)于南京大學(xué),，現(xiàn)任中國生物化學(xué)與分子生物學(xué)學(xué)會(huì)副理事長兼秘書長；中國細(xì)胞生物學(xué)學(xué)會(huì)理事；上海生物化學(xué)與分子生物學(xué)學(xué)會(huì)理事長,；中國神經(jīng)科學(xué)學(xué)會(huì)神經(jīng)化學(xué)專業(yè)委員會(huì)主任委員。近年來主要研究方向?yàn)楦杉?xì)胞與神經(jīng)的發(fā)育研究,。
BMP與Wnt/β-catenin信號(hào)是胚胎發(fā)育過程中重要的調(diào)控信號(hào),，這些信號(hào)途徑的調(diào)控異常會(huì)導(dǎo)致胚胎發(fā)育的紊亂甚至誘發(fā)癌癥，因此對BMP和Wnt/β-catenin信號(hào)的調(diào)節(jié)機(jī)制研究具有重要的生物學(xué)意義,。在脊髓背側(cè)的神經(jīng)發(fā)育過程中,，BMP與Wnt/β-catenin信號(hào)通路是維持VZ區(qū)(ventricular zone)中的神經(jīng)前體細(xì)胞增殖所必須的，而在MZ區(qū)(mantle zone)中這兩種信號(hào)的活性應(yīng)受到抑制,，以保證這些細(xì)胞退出細(xì)胞周期并分化為功能神經(jīng)元,。但是，在由VZ區(qū)向MZ區(qū)發(fā)育分化過程中，BMP與Wnt/β-catenin信號(hào)活性調(diào)控的分子機(jī)制并不清楚,。
研究人員發(fā)現(xiàn)在雞胚神經(jīng)管發(fā)育過程中,，BMP信號(hào)通路負(fù)性調(diào)節(jié)因子Smad6特異表達(dá)于其背側(cè)VZ與MZ區(qū)之間的IZ區(qū)intermediate zone)，Smad6不僅抑制BMP信號(hào)通路,，還同時(shí)干擾Wnt/β-catenin信號(hào)活性,。進(jìn)一步研究發(fā)現(xiàn)，Smad6招募轉(zhuǎn)錄抑制因子CtBP與β-catenin/TCF4形成轉(zhuǎn)錄抑制復(fù)合物,，直接抑制Wnt/β-catenin下游基因的表達(dá),，進(jìn)而促進(jìn)分化中的神經(jīng)元由增殖向分化狀態(tài)轉(zhuǎn)換。
該研究首次發(fā)現(xiàn)了Smad6在脊髓背側(cè)神經(jīng)發(fā)育過程中的功能,，并揭示其調(diào)控作用的分子機(jī)制,，增強(qiáng)了人們對胚胎神經(jīng)發(fā)育機(jī)制的理解。
該項(xiàng)工作得到了國家科技部,、國家自然科學(xué)基金委,、中國科學(xué)院以及上海市科委的經(jīng)費(fèi)支持。（生物谷Bioon.com）
生物谷推薦原文出處：
Proceedings of the National Academy of Sciences DOI： 10.1073/pnas.1100160108
Smad6 promotes neuronal differentiation in the intermediate zone of the dorsal neural tube by inhibition of the Wnt/β-catenin pathway
Xie, Zhihui; Chen, Yongfeng; Li, Zhenfei; Bai, Ge; Zhu, Yue; Yan, Rui; Tan, Fangzhi; Chen, Ye-Guang; Guillemot, Francois; Li, Lin; Jing, Naihe
Proliferation of the neural/neuronal progenitor cells (NPCs) at the ventricular zone of the dorsal spinal cord requires thestimuli of Wnt and bone morphogenic protein (BMP). However, how these two signaling pathways are regulated to initiate differentiationin the NPCs as they enter the intermediate zone is not known. Here, we show that Smad6, a negative regulator of BMP signaling,is expressed in the intermediate zone of the chick dorsal spinal cord. Knockdown experiments show that Smad6 is required forpromoting NPCs to exit the cell cycle and differentiate into neurons. Although we find that Smad6 inhibits BMP signaling,as expected, we also find that Smad6 unexpectedly inhibits the Wnt/β-catenin pathway. The inhibition of the Wnt/β-cateninpathway by Smad6 is independent of its effect on the BMP pathway. Rather, Smad6 through its N-terminal domain and link regionenhances the interaction of C-terminal binding protein with the β-catenin/T cell factor (TCF) complex and the TCF-bindingelement to inhibit β-catenin–mediated transcriptional activation. Our study provides evidence that transition of NPCs froma proliferative state to a differentiating state is controlled by the dual inhibitory role of Smad6 to both BMP and Wnt signalingat the level of transcription.
