Gtf2i-encoded transcription factor Tfii-i regulates myelination via Sox10 and Mbp regulatory elements

The transcriptional regulatory network governing the differentiation and functionality of oligodendrocytes is essential for the formation and maintenance of the myelin sheath, and hence for the proper function of the nervous system. Perturbations in the intricate interplay of transcriptional effectors within this network can lead to a variety of nervous system pathologies. In this study, we have identified Gtf2i-encoded general transcription factor II-I (Tfii-i), as a regulator of key myelination-related genes. Gtf2i deletion from myelinating glia cells in mice led to functional alterations in CNS myelin, including elevated mRNA and protein expression levels of the central myelin component Mbp, enhanced connectivity properties, and thicker myelin wrapping axons with increased diameters. These changes resulted in faster axonal conduction across the corpus callosum, and improved motor coordination. In the PNS, Gtf2i deletion from Schwann cells led to hypermyelination of the tibial branch of the sciatic nerve. Furthermore, we show that, in myelinating oligodendrocytes, Tfii-i directly binds to regulatory elements of Sox10 and Mbp. These findings add to our understanding of myelination regulation and specifically elucidate a cell-autonomous mechanism for Tfii-i in myelinating glia transcriptional network.