Function of zinc finger protein 276 during CNS myelination and remyelination as part of the oligodendrocyte transcriptional network
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Efficient and fast signal transduction within the central nervous system (CNS) relies on the insulation of neuronal axons by specialized glial cells, the myelinating oligodendrocytes. Oligodendrocyte differentiation and developmental myelination of axons are tightly regulated by an elaborate transcriptional regulatory network. In this project we uncovered regulatory functions of a previously unstudied transcriptional regulator, Zfp276, in the aforementioned processes. Zfp276 is specifically expressed in mature oligodendrocytes within the CNS and is under the control of Sox10, a key transcriptional regulator of oligodendrocyte differentiation and CNS myelination. We found that after deletion of Sox10 in oligodendrocytes of the mouse CNS, levels of Zfp276 dramatically decrease, indicating its dependency on Sox10. Additionally, Sox10 was able to activate a newly identified regulatory region within the Zfp276 genomic locus in reporter gene assays. To understand the functions of Zfp276 during oligodendrocyte differentiation and CNS myelination, we generated mice in which Zfp276 expression was specifically deleted from the oligodendrocyte lineage. In these mice, we observed a delay in the maturation of oligodendrocytes and developmental myelination, particularly during early postnatal stages, suggesting a positive role for Zfp276 in regulating oligodendrocyte differentiation. Vice versa, cell culture experiments additionally showed that forced overexpression of Zfp276 in primary oligodendroglial cells induces faster differentiation and decreases their proliferation rate. Further investigation revealed that Zfp276 acts by inhibiting the expression of genes associated with maintaining oligodendrocyte progenitor cells in an immature state, while not affecting the expression of genes related to myelin formation. Mechanistically, Zfp276 exerts its functions by directly binding to specific consensus sites within regulatory regions of its target genes, thereby repressing the Sox10- dependent gene expression together with its interaction partner Zeb2. This discovery highlights Zfp276 as a critical regulator of oligodendrocyte differentiation and myelination in the CNS. By fine-tuning the balance between proliferation and differentiation of oligodendrocyte precursors, Zfp276 ensures the timely onset of myelination. Understanding the intricate mechanisms underlying myelination is essential for developing therapies for disorders involving myelin dysfunction, such as multiple sclerosis and leukodystrophies. The identification of Zfp276 as a novel player in this process opens up new avenues for therapeutic intervention and underscores the importance of transcriptional regulation in nervous system development and function.
Publications
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Crazy Little Thing Called Sox—New Insights in Oligodendroglial Sox Protein Function. International Journal of Molecular Sciences, 20(11), 2713.
Wittstatt, Jan; Reiprich, Simone & Küspert, Melanie
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15th European Meeting on Glial Cells in Health and Disease (Marseille, France, July 5–9 2021): Title: “Zinc-finger transcription factor Zfp276 acts as a novel regulator of oligodendroglial differentiation”
Tim Aberl
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Transcription factor Zfp276 drives oligodendroglial differentiation and myelination by switching off the progenitor cell program. Nucleic Acids Research, 50(4), 1951-1968.
Aberle, Tim; Piefke, Sandra; Hillgärtner, Simone; Tamm, Ernst R.; Wegner, Michael & Küspert, Melanie
