Gtf2i-encoded transcription factor Tfii-i regulates myelination

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. To assess how Tfii-i absence from oligodendrocytes alters myelin properties on a molecular level, we compared the biochemically-enriched myelin fraction purified from brains of Gtf2i-KO and control mice by label-free quantitative mass spectrometry using the MSE-type data-independent acquisition (DIA) mode. We found an increased protein abundance of several key myelin proteins such as Mbp and Mog, while the abundance of Gpr37 was decreased, overall indicating a molecular hypermyelination phenotype in the absence of Tfii-i. These results, together with findings from - among others - structural, electrophysiological and behavioral approaches, show that Gtf2i deletion from myelinating glia cells in mice led to functional alterations in CNS myelin, which resulted in faster axonal conduction and improved motor coordination.