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HDAC1 and HDAC2 control the transcriptional program of myelination and the survival of Schwann cells

Nature Neuroscience volume 14, pages 429–436 (2011)Cite this article

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Abstract

Histone deacetylases (HDACs) are major epigenetic regulators. We show that HDAC1 and HDAC2 functions are critical for myelination of the peripheral nervous system. Using mouse genetics, we have ablated Hdac1 and Hdac2 specifically in Schwann cells, resulting in massive Schwann cell loss and virtual absence of myelin in mutant sciatic nerves. Expression of Sox10 and Krox20, the main transcriptional regulators of Schwann cell myelination, was greatly reduced. We demonstrate that in Schwann cells, HDAC1 and HDAC2 exert specific primary functions: HDAC2 activates the transcriptional program of myelination in synergy with Sox10, whereas HDAC1 controls Schwann cell survival by regulating the levels of active β-catenin.

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Figure 1: Partial axonal sorting delay, absence of myelination and massive Schwann cell loss in H1/2−/− nerves.
Figure 2: In sciatic nerves and long term–transduced RSCs, loss of HDAC1 induces upregulation of HDAC2, and vice versa, whereas in H2+/− or H1+/− sciatic nerves and in short term–transduced cells, expression of the targeted HDAC is reduced without substantial upregulation of the untargeted HDAC.
Figure 3: HDAC2 is an inducer of Schwann cell differentiation.
Figure 4: Transcriptional regulation of the myelination program by HDACs.
Figure 5: Increased activation of the Wnt/β-catenin pathway induces Schwann cell apoptosis and HDAC1 maintains survival by limiting the levels of ABC.
Figure 6: Sox10 upregulates ABC and ABC promotes the expression of differentiation markers in Schwann cells.

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Acknowledgements

We thank M. Wegner (Universtät Erlangen-Nürnberg), E. Seto (Moffitt Cancer Center), S. Schreiber (Harvard University), Z. Werb and B. Welm (University of Utah), J. Crabtree (Stanford University), T. Reya (Duke University Medical Center), W.J. Pavan (US National Institutes of Health), A. McCallion and M. Prasad (Johns Hopkins University School of Medicine) and D.R. Colman (McGill University) for providing constructs and antibodies, T. Meier, W. Seufert and N. Mantei for critically reading the manuscript and the Functional Genomic Center Zurich for gene array analyses. These studies were supported by two Swiss National Science Foundation (SNSF) grants, a Marie-Heim Vögtlin subsidy (PMPDP3_122738/1) to C. Jacob, and another SNSF grant to U. Suter, and by a grant from the Swiss National Center for Competence in Research (NCCR) Neural Plasticity and Repair to U. Suter. The work in the laboratory of P. Matthias was supported by the Novartis Research Foundation.

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Author notes

  1. Carlos N Christen, Jorge A Pereira and Christian Somandin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, Institute of Cell Biology, ETH Zurich, Zurich, Switzerland

    Claire Jacob, Carlos N Christen, Jorge A Pereira, Christian Somandin, Arianna Baggiolini, Pirmin Lötscher, Murat Özçelik, Nicolas Tricaud & Ueli Suter

  2. Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

    Dies Meijer

  3. Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland

    Teppei Yamaguchi & Patrick Matthias

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Contributions

C.J. designed the study, analyzed the data and wrote the manuscript; C.J., C.N.C., J.A.P., C.S., A.B, P.L., M.O. and N.T. performed and analyzed the experiments; D.M., T.Y. and P.M. generated and provided crucial mouse lines and support; U.S. conceived and supervised the study and co-wrote the manuscript. All authors commented on the manuscript.

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Correspondence to Claire Jacob or Ueli Suter.

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Jacob, C., Christen, C., Pereira, J. et al. HDAC1 and HDAC2 control the transcriptional program of myelination and the survival of Schwann cells. Nat Neurosci 14, 429–436 (2011). https://doi.org/10.1038/nn.2762

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