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 highthroughput 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. K E Y W O R D S network biology, ODE mathematical model, Oligodendrocytes, TF-miRNA circuits, TFregulated feedforward loop 1 | INTRODUCTION Rapid information processing in the vertebrate central nervous system (CNS) is dependent on saltatory conduction as a consequence of axonal ensheathment by myelin-producing glial cells (Nave & Werner, 2014).Developmental disturbances in myelin production (i.e., dysmyelination) or impairment of myelin sheaths (i.e., demyelination) are typical hallmarks of neurodegenerative diseases in humans including leukodystrophies and Multiple Sclerosis. Oligodendrocytes (OLs) are the myelin-forming glial cells of the CNS that originate from embryonic neuroepithelial stem cells located at the ventricular zone of the developing spinal cord. OLs are generated from OL precursor cells (OPCs) that are derived from these germinal zones, undergoing a number of developmental stages followed by terminal differentiation and initiation of myelin production (Rowitch, 2004).Myelination is a complex process and requires appropriate coordination and organization of downstream gene regulatory and metabolic processes. For example, genes encoding for myelin proteins are already expressed in the progenitor stages during development, followed by their protein synthesis during OL maturation, and the Abbreviations: FPKM, fragment per kilobase of exon per million fragments