近日來自中國科學院上海生命科學研究院生物化學與細胞生物學研究所的研究人員在新研究中揭示了Smad6調控Wnt/β-catenin信號通路的分子機制,，及其在脊髓背側神經元分化過程中的功能。相關研究論文于7月5日發(fā)表在國際重要學術期刊美國《國家科學院院刊》(PNAS)上,。
這項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下完成。后者早年畢業(yè)于南京大學,，現任中國生物化學與分子生物學學會副理事長兼秘書長,；中國細胞生物學學會理事；上海生物化學與分子生物學學會理事長,；中國神經科學學會神經化學專業(yè)委員會主任委員,。近年來主要研究方向為干細胞與神經的發(fā)育研究。
BMP與Wnt/β-catenin信號是胚胎發(fā)育過程中重要的調控信號,，這些信號途徑的調控異常會導致胚胎發(fā)育的紊亂甚至誘發(fā)癌癥,，因此對BMP和Wnt/β-catenin信號的調節(jié)機制研究具有重要的生物學意義。在脊髓背側的神經發(fā)育過程中,，BMP與Wnt/β-catenin信號通路是維持VZ區(qū)(ventricular zone)中的神經前體細胞增殖所必須的,，而在MZ區(qū)(mantle zone)中這兩種信號的活性應受到抑制，以保證這些細胞退出細胞周期并分化為功能神經元,。但是,，在由VZ區(qū)向MZ區(qū)發(fā)育分化過程中，BMP與Wnt/β-catenin信號活性調控的分子機制并不清楚,。
研究人員發(fā)現在雞胚神經管發(fā)育過程中,，BMP信號通路負性調節(jié)因子Smad6特異表達于其背側VZ與MZ區(qū)之間的IZ區(qū)intermediate zone)，Smad6不僅抑制BMP信號通路,，還同時干擾Wnt/β-catenin信號活性,。進一步研究發(fā)現，Smad6招募轉錄抑制因子CtBP與β-catenin/TCF4形成轉錄抑制復合物,，直接抑制Wnt/β-catenin下游基因的表達,，進而促進分化中的神經元由增殖向分化狀態(tài)轉換。
該研究首次發(fā)現了Smad6在脊髓背側神經發(fā)育過程中的功能,，并揭示其調控作用的分子機制,，增強了人們對胚胎神經發(fā)育機制的理解。
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費支持。（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.
