Premium
A gene regulatory architecture that controls region‐independent dynamics of oligodendrocyte differentiation
Author(s) -
Cantone Martina,
Küspert Melanie,
Reiprich Simone,
Lai Xin,
Eberhardt Martin,
Göttle Peter,
Beyer Felix,
Azim Kasum,
Küry Patrick,
Wegner Michael,
Vera Julio
Publication year - 2019
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23569
Subject(s) - sox10 , biology , olig2 , gene regulatory network , transcription factor , oligodendrocyte , feed forward , sox2 , cellular differentiation , regulation of gene expression , computational biology , neuroscience , myelin , gene , gene expression , genetics , central nervous system , control engineering , engineering
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.