Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.
Nucleic Acids Res. 2012 Jan;40(1):88-101. doi: 10.1093/nar/gkr734. Epub 2011 Sep 9.
The Sox10 transcription factor is a central regulator of vertebrate neural crest and nervous system development. Its expression is likely controlled by multiple enhancer elements, among them U3 (alternatively known as MCS4). Here we analyze U3 activity to obtain deeper insights into Sox10 function and expression in the neural crest and its derivatives. U3 activity strongly depends on the presence of Sox10 that regulates its own expression as commonly observed for important developmental regulators. Sox10 bound directly as monomer to at least three sites in U3, whereas a fourth site preferred dimers. Deletion of these sites efficiently reduced U3 activity in transfected cells and transgenic mice. In stimulating the U3 enhancer, Sox10 synergized with many other transcription factors present in neural crest and developing peripheral nervous system including Pax3, FoxD3, AP2α, Krox20 and Sox2. In case of FoxD3, synergism involved Sox10-dependent recruitment to the U3 enhancer, while Sox10 and AP2α each had to bind to the regulatory region. Our study points to the importance of autoregulatory activity and synergistic interactions for maintenance of Sox10 expression and functional activity of Sox10 in the neural crest regulatory network.
Sox10 转录因子是脊椎动物神经嵴和神经系统发育的核心调控因子。其表达可能受到多个增强子元件的控制，其中包括 U3（也称为 MCS4）。在这里，我们分析了 U3 的活性，以更深入地了解 Sox10 在神经嵴及其衍生物中的功能和表达。U3 的活性强烈依赖 Sox10 的存在，这与重要发育调节剂的常见情况一样，Sox10 调节自身的表达。Sox10 作为单体直接结合到 U3 中的至少三个位点，而第四个位点则偏爱二聚体。这些位点的缺失有效地降低了转染细胞和转基因小鼠中 U3 的活性。在刺激 U3 增强子时，Sox10 与神经嵴和发育中的周围神经系统中存在的许多其他转录因子（包括 Pax3、FoxD3、AP2α、Krox20 和 Sox2）协同作用。就 FoxD3 而言，协同作用涉及 Sox10 依赖性募集到 U3 增强子，而 Sox10 和 AP2α 各自必须结合到调节区。我们的研究表明，对于 Sox10 在神经嵴调控网络中的表达和功能活性的维持，自调节活性和协同相互作用非常重要。
