摘要：7月5日，国际重要学术期刊美国《国家科学院院刊》（PNAS）发表了中科院上海生命科学研究院生化与细胞所景乃禾研究组的最新研究成果，揭示了Smad6调控Wnt/β-catenin信号通路的分子机制，及其在脊髓背侧神经元分化过程中的功能。这项工作主要由博士研究生谢治慧、陈永峰等在景乃禾研究员的指导下完成。
BMP与Wnt/β-catenin信号是胚胎发育过程中重要的调控信号，这些信号途径的调控异常会导致胚胎发育的紊乱甚至诱发癌症，因此对BMP和Wnt/β-catenin信号的调节机制研究具有重要的生物学意义。在脊髓背侧的神经发育过程中，BMP与Wnt/β-catenin信号通路是维持VZ区（ventricular zone）中的神经前体细胞增殖所必须的，而在MZ区（mantle zone）中这两种信号的活性应受到抑制，以保证这些细胞退出细胞周期并分化为功能神经元。但是，在由VZ区向MZ区发育分化过程中，BMP与Wnt/β-catenin信号活性调控的分子机制并不清楚。
景乃禾研究组谢治慧、陈永峰博士等发现，在鸡胚神经管发育过程中，BMP信号通路负性调节因子Smad6特异表达于其背侧VZ与MZ区之间的IZ区 (intermediate zone)，Smad6不仅抑制BMP信号通路，还同时干扰Wnt/β-catenin信号活性。进一步研究发现，Smad6招募转录抑制因子CtBP与β-catenin/TCF4形成转录抑制复合物，直接抑制Wnt/β-catenin下游基因的表达，进而促进分化中的神经元由增殖向分化状态转换。
该研究首次发现了Smad6在脊髓背侧神经发育过程中的功能，并揭示其调控作用的分子机制，增强了人们对胚胎神经发育机制的理解。
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。
在脊髓背侧神经发育过程中起调控作用的Smad6分子
生物探索推荐英文论文摘要：
doi: 10.1073/pnas.1100160108
PNAS July 5, 2011
Smad6 promotes neuronal differentiation in the intermediate zone of the dorsal neural tube by inhibition of the Wnt/β-catenin pathway
Abstract
Proliferation of the neural/neuronal progenitor cells (NPCs) at the ventricular zone of the dorsal spinal cord requires the stimuli of Wnt and bone morphogenic protein (BMP). However, how these two signaling pathways are regulated to initiate differentiation in 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 for promoting 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-catenin pathway by Smad6 is independent of its effect on the BMP pathway. Rather, Smad6 through its N-terminal domain and link region enhances the interaction of C-terminal binding protein with the β-catenin/T cell factor (TCF) complex and the TCF-binding element to inhibit β-catenin–mediated transcriptional activation. Our study provides evidence that transition of NPCs from a proliferative state to a differentiating state is controlled by the dual inhibitory role of Smad6 to both BMP and Wnt signaling at the level of transcription.
