Laboratoire d'Embryologie Moléculaire, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium.
EMBO J. 2010 Jan 6;29(1):55-67. doi: 10.1038/emboj.2009.313. Epub 2009 Oct 22.
A complex set of extracellular signals is required for neural crest (NC) specification. However, how these signals function to coordinate cell-cycle progression and differentiation remains poorly understood. Here, we report in Xenopus a role for the transcription factor signal transducers and activators of transcription-3 (Stat3) in this process downstream of FGF signalling. Depletion of Stat3 inhibits NC gene expression and cell proliferation, whereas overexpression expands the NC domain and promotes cell proliferation. Stat3 is phosphorylated and activated in ectodermal cells by FGFs through binding with FGFR4. Stat3 activation is also modulated by Hairy2 and Id3 proteins that, respectively, facilitate and disrupt Stat3-FGFR4 complex formation. Furthermore, distinct levels of Stat3 activity control Hairy2 and Id3 transcription, leading to Stat3 self-regulation. Finally, high Stat3 activity maintains cells in an undifferentiated state, whereas low activity promotes cell proliferation and NC differentiation. Together, our data suggest that Stat3, downstream of FGFs and under the positive and negative feedback regulation of Hairy2 and Id3, plays an essential role in the coordination of cell-cycle progression and differentiation during NC specification.
一组复杂的细胞外信号对于神经嵴（NC）的特化是必需的。然而，这些信号如何协调细胞周期进程和分化仍然知之甚少。在这里，我们在非洲爪蟾中报告了转录因子信号转导子和转录激活子 3（Stat3）在 FGF 信号下游的这个过程中的作用。Stat3 的耗竭抑制 NC 基因表达和细胞增殖，而过表达则扩大 NC 区域并促进细胞增殖。Stat3 通过与 FGFR4 结合，在表皮细胞中被 FGFs 磷酸化和激活。Hairy2 和 Id3 蛋白也调节 Stat3 激活，它们分别促进和破坏 Stat3-FGFR4 复合物的形成。此外，不同水平的 Stat3 活性控制 Hairy2 和 Id3 的转录，从而实现 Stat3 的自我调控。最后，高 Stat3 活性使细胞保持未分化状态，而低活性则促进细胞增殖和 NC 分化。总之，我们的数据表明，Stat3 在 FGFs 的下游，在 Hairy2 和 Id3 的正反馈和负反馈调节下，在神经嵴特化过程中协调细胞周期进程和分化中发挥着重要作用。
