Abstract
Fast axonal conduction depends on myelin, which is formed by Schwann cells in the PNS. We found that the transcription factor Yin Yang 1 (YY1) is crucial for peripheral myelination. Conditional ablation of Yy1 in the Schwann cell lineage resulted in severe hypomyelination, which occurred independently of altered Schwann cell proliferation or apoptosis. In Yy1 mutant mice, Schwann cells established a 1:1 relationship with axons but were unable to myelinate them. The Schwann cells expressed low levels of myelin proteins and of Egr2 (also called Krox20), which is an important regulator of peripheral myelination. In vitro, Schwann cells that lacked Yy1 did not upregulate Egr2 in response to neuregulin1 and did not express myelin protein zero. This phenotype was rescued by overexpression of Egr2. In addition, neuregulin-induced phosphorylation of YY1 was required for transcriptional activation of Egr2. Thus, YY1 emerges as an important activator of peripheral myelination that links neuregulin signaling with Egr2 expression.
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Acknowledgements
We thank Y. Shi, K.A. Nave and B. Popko for mouse lines; G. Crabtree, D. Meijer and M. Grumet for plasmids and antibodies; H. Kim and P. Maurel for advice on Schwann cell and myelination cultures; C. Krier for assistance with microarrays; J. Salzer, K. Jessen, P. Brophy and C. Taveggia for discussions; and N. Kuo, J. Li and R. Srinivasan for technical assistance. This work was supported by grant numbers 5R01NS042925-08, R01NS052738-04 and NS04295-08S ARRA supplement and NMSS RG-4134 to P.C. and in part by the NJ Commission on Spinal Cord Research (08B-010-SCR3 to Y.H.). Electron microscopy was performed at the VCU Department of Anatomy and Neurobiology Microscopy Facility and supported, in part, by funding from a US National Institutes of Health Natinal Institute of Neurological Disorders and Stroke Center core grant (5P30NS047463-02).
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Y.H. conducted the majority of the experiments and analyzed the data. J.Y.K. generated the YY1 point mutation plasmids and performed the immunoprecipitation and western blots. J.D. performed the ultrastructural analysis of the sciatic nerve. C.M.-V. and A.T. helped with the DRG co-culture experiments and conducted part of the in vitro myelination studies. J.S. performed the conservation analysis and contributed to the analysis of gene expression in the three mutants. P.C. supervised the project, analyzed the data, formatted the figures, uploaded microarray data and wrote the manuscript.
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He, Y., Kim, J., Dupree, J. et al. Yy1 as a molecular link between neuregulin and transcriptional modulation of peripheral myelination. Nat Neurosci 13, 1472–1480 (2010). https://doi.org/10.1038/nn.2686
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DOI: https://doi.org/10.1038/nn.2686
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