Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes

• Published in: Nature neuroscience Vol. 17; no. 10; pp. 1322 - 1329
• Main Authors: Glasgow, Stacey M, Zhu, Wenyi, Stolt, C Claus, Huang, Teng-Wei, Chen, Fuyi, LoTurco, Joseph J, Neul, Jeffrey L, Wegner, Michael, Mohila, Carrie, Deneen, Benjamin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2014; Nature Publishing Group
• Subjects: 38/15; 38/32; 631/136; 631/378/2582; 631/378/2596/1308; 631/378/2596/1705; 64/110; 82/1; 82/51; Animal Genetics and Genomics; Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors - metabolism; Behavioral Sciences; Biological Techniques; Biomedicine; Brain cancer; Cell Differentiation - drug effects; Cells, Cultured; Cerebral Cortex - cytology; Chick Embryo; Chromatin Immunoprecipitation; Development and progression; Diversification; Electroporation; Embryo, Mammalian; Gene expression; Genetic aspects; Glioma - classification; Glioma - genetics; Glioma - metabolism; Gliomas; Green Fluorescent Proteins - genetics; Homeodomain Proteins - metabolism; Medical schools; Medicine; Mice; Myelin Basic Protein - genetics; Myelin Basic Protein - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Neuroglia - drug effects; Neuroglia - metabolism; Neurosciences; NFI Transcription Factors - genetics; NFI Transcription Factors - metabolism; Oligodendrocyte Transcription Factor 2; Physiology; Properties; SOXE Transcription Factors - genetics; SOXE Transcription Factors - metabolism; Spinal cord; Transcription factors; Transfection; United States > US; Texas
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.3790

Sox10 and Nuclear Factor I-A (NFIA) are transcriptional regulators of oligodendrocyte and astrocyte generation in the mammalian brain, respectively. This study describes reciprocal antagonism between these transcription factors whereby NFIA directly antagonizes Sox10 regulation of myelin gene expression in oligodendrocytes, and Sox10 negatively regulates NFIA during astrocyte differentiation. The work also demonstrates this mutual antagonism being involved in tumorigenesis, particularly during oligodendroglioma to astrocytoma conversion. Lineage progression and diversification is regulated by the coordinated action of unique sets of transcription factors. Oligodendrocytes (OL) and astrocytes (AS) comprise the glial sub-lineages in the CNS, and the manner in which their associated regulatory factors orchestrate lineage diversification during development and disease remains an open question. Sox10 and NFIA are key transcriptional regulators of gliogenesis associated with OL and AS. We found that NFIA inhibited Sox10 induction of OL differentiation through direct association and antagonism of its function. Conversely, we found that Sox10 antagonized NFIA function and suppressed AS differentiation in mouse and chick systems. Using this developmental paradigm as a model for glioma, we found that this relationship similarly regulated the generation of glioma subtypes. Our results describe the antagonistic relationship between Sox10 and NFIA that regulates the balance of OL and AS fate during development and demonstrate for the first time, to the best of our knowledge, that the transcriptional processes governing glial sub-lineage diversification oversee the generation of glioma subtypes.