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Glia. 2019 May;67(5):825-843. doi: 10.1002/glia.23569. Epub 2019 Feb 7.

A gene regulatory architecture that controls region-independent dynamics of oligodendrocyte differentiation.

Author information

1
Laboratory of Systems Tumor Immunology, Hautklinik, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
2
Faculty of Mechanical Engineering, Specialty Division for Systems Biotechnology, Technische Universität München, Munich, Germany.
3
Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
4
Neuroregeneration, Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.

Abstract

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.

KEYWORDS:

ODE mathematical model; Oligodendrocytes; TF-miRNA circuits; TF-regulated feedforward loop; network biology

PMID:
30730593
DOI:
10.1002/glia.23569

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