The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Cell Res. 2010 Dec;20(12):1306-18. doi: 10.1038/cr.2010.158. Epub 2010 Nov 16.
Although Activin/Nodal signaling regulates pluripotency of human embryonic stem (ES) cells, how this signaling acts in mouse ES cells remains largely unclear. To investigate this, we confirmed that mouse ES cells possess active Smad2-mediated Activin/Nodal signaling and found that Smad2-mediated Activin/Nodal signaling is dispensable for self-renewal maintenance but is required for proper differentiation toward the mesendoderm lineage. To gain insights into the underlying mechanisms, Smad2-associated genes were identified by genome-wide chromatin immunoprecipitation-chip analysis. The results showed that there is a transcriptional correlation between Smad2 binding and Activin/Nodal signaling modulation, and that the development-related genes were enriched among the Smad2-bound targets. We further identified Tapbp as a key player in mesendoderm differentiation of mouse ES cells acting downstream of the Activin/Nodal-Smad2 pathway. Taken together, our findings suggest that Smad2-mediated Activin/Nodal signaling orchestrates mesendoderm lineage commitment of mouse ES cells through direct modulation of corresponding developmental regulator expression.
虽然激活素/Nodal 信号通路调控人胚胎干细胞（ES 细胞）的多能性，但该信号通路在小鼠 ES 细胞中的作用仍不清楚。为了研究这一问题，我们证实小鼠 ES 细胞具有活跃的 Smad2 介导的激活素/Nodal 信号通路，并发现 Smad2 介导的激活素/Nodal 信号通路对于自我更新维持不是必需的，但对于向中胚层谱系的适当分化是必需的。为了深入了解潜在的机制，我们通过全基因组染色质免疫沉淀芯片分析鉴定了与 Smad2 相关的基因。结果表明，Smad2 结合与激活素/Nodal 信号通路调节之间存在转录相关性，并且 Smad2 结合的靶点中富含与发育相关的基因。我们进一步鉴定出 Tapbp 是激活素/Nodal-Smad2 通路下游调控小鼠 ES 细胞中中胚层分化的关键因子。综上所述，我们的研究结果表明，Smad2 介导的激活素/Nodal 信号通路通过直接调节相应的发育调控因子的表达来协调小鼠 ES 细胞的中胚层谱系决定。
