Laboratory of Systems Tumor Immunology, Hautklinik, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Faculty of Mechanical Engineering, Specialty Division for Systems Biotechnology, Technische Universität München, Munich, Germany.
Glia. 2019 May;67(5):825-843. doi: 10.1002/glia.23569. Epub 2019 Feb 7.
Oligodendrocytes (OLs) facilitate information processing in the vertebrate central nervous system via axonal ensheathment. The structure and dynamics of the regulatory network that mediates oligodendrogenesis are poorly understood. We employed bioinformatics and meta-analysis of high-throughput datasets to reconstruct a regulatory network underpinning OL differentiation. From this network, we identified families of feedforward loops comprising the transcription factors (TFs) Olig2, Sox10, and Tcf7l2 and their targets. Among the targets, we found eight other TFs related to OL differentiation, suggesting a hierarchical architecture in which some TFs (Olig2, Sox10, and Tcf7l2) regulate via feedforward loops the expression of others (Sox2, Sox6, Sox11, Nkx2-2, Nkx6-2, Hes5, Myt1, and Myrf). Model simulations with a kinetic model reproduced the mechanisms of OL differentiation only when in the model, Sox10-mediated repression of Tcf7l2 by miR-338/miR-155 was introduced, a prediction confirmed in genetic functional experiments. Additional model simulations suggested that OLs from dorsal regions emerge through BMP/Sox9 signaling.
少突胶质细胞（OLs）通过轴突包绕来促进脊椎动物中枢神经系统中的信息处理。介导少突胶质发生的调节网络的结构和动态尚不清楚。我们采用生物信息学和高通量数据集的元分析来重建支持 OL 分化的调节网络。从这个网络中，我们确定了包含转录因子（TFs）Olig2、Sox10 和 Tcf7l2 及其靶标的前馈环家族。在这些靶标中，我们发现了另外 8 个与 OL 分化相关的 TF，表明存在一种分层结构，其中一些 TF（Olig2、Sox10 和 Tcf7l2）通过前馈环调节其他 TF（Sox2、Sox6、Sox11、Nkx2-2、Nkx6-2、Hes5、Myt1 和 Myrf）的表达。使用动力学模型进行的模型模拟仅在模型中引入 Sox10 通过 miR-338/miR-155 对 Tcf7l2 的抑制时，才能再现 OL 分化的机制，这一预测在遗传功能实验中得到了证实。额外的模型模拟表明，来自背侧区域的 OL 通过 BMP/Sox9 信号出现。
