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Yy1 as a molecular link between neuregulin and transcriptional modulation of peripheral myelination

Nature Neuroscience volume 13, pages 1472–1480 (2010)Cite this article

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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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Figure 1: Peripheral nerve hypomyelination in mice with conditional ablation of Yy1.
Figure 2: Ablation of Yy1 impairs the ability of Schwann cells to myelinate.
Figure 3: Effect of Yy1 ablation on the ability of Schwann cells to myelinate in vitro.
Figure 4: Ablation of Yy1 modulates Schwann cell S-phase entry during the second week of development.
Figure 5: YY1 regulates Egr2 expression.
Figure 6: YY1 regulates Egr2 expression in response to NRG1.
Figure 7: YY1 binds to chromatin at the Egr2 locus only in Schwann cells treated with NRG1.
Figure 8: The regulation of Egr2 by phosphorylated YY1 is mediated by NRG1-dependent MEK activation.

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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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Authors and Affiliations

  1. Department of Neuroscience and Genetics and Genomics, Mount Sinai School of Medicine, New York, New York, USA

    Ye He, Jin Young Kim & Patrizia Casaccia

  2. Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia, USA

    Jeffrey Dupree

  3. Department of Cell Biology, Hunter College, New York, New York, USA

    Ambika Tewari & Carmen Melendez-Vasquez

  4. Department of Comparative Biosciences and Waisman Center, University of Wisconsin, Madison, Wisconsin, USA

    John Svaren

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Contributions

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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Correspondence to Patrizia Casaccia.

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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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