NATURE NEUROSCIENCE VOLUME 14 | NUMBER 4 | APRIL 2011 429 ARTICLES HDACs are chromatin-remodeling proteins. They exert epigenetic regulations by removing acetyl groups from histone tails, favor- ing condensed chromatin architecture that is less accessible for transcription factors. HDACs are commonly believed to act as transcriptional co-repressors 1–3 but they can also contribute to tran- scriptional activation 4,5 . In addition, HDACs act non-epigenetically by deacetylating non-histone targets 6 , including various transcrip- tion factors, implying that HDACs regulate transcriptional activity at different levels. HDACs are of particular interest to neurobiol- ogists because HDAC inhibitors enhance neural regeneration 7,8 and control oligodendrocyte differentiation 9–11 . In contrast to oligodendrocytes in the CNS, Schwann cells, the myelination- competent cells of the peripheral nervous system (PNS), promote regeneration of damaged PNS and CNS axons and are contemplated in transplantation-based repair strategies after CNS injury 12 . In addition, Schwann cells are affected by common tumors 13 and in peripheral neuropathies 14 . Thus, a detailed understanding of Schwann cell biology is of major importance for uncovering their regenerative properties and developing efficient repair of damage to the CNS and PNS, and for treatment of peripheral nerve tumors and peripheral neuropathies. Here we show that HDAC1 and HDAC2 are essential for Schwann cell myelination and survival: HDAC1 maintains Schwann cell sur- vival by limiting the levels of active β-catenin (ABC), and HDAC2 is an inducer of the transcriptional program of myelination. RESULTS HDAC1 and HDAC2 control Schwann cell myelination and survival HDAC1 and HDAC2, coexpressed in Schwann cell nuclei (Supplementary Fig. 1a–d), were upregulated at postnatal day 1 (P1) and remained high until P5 in mouse sciatic nerves (referred to as nerves hereafter; Supplementary Fig. 1e), suggesting postnatal functions of these proteins. To determine their functions, we depleted HDAC1 and/or HDAC2 in Schwann cells using loxP-flanked Hdac1 and/or Hdac2 alleles 15 and mice expressing the Cre recombinase under control of Desert Hedgehog gene regulatory elements (Dhh Cre ). Dhh Cre is active in developing PNS glial cells, but not in neural crest cells or neurons 16,17 . Dhh Cre Hdac1 or Hdac2 homozygous knockout mice (H1 −/− or H2 −/− ) were indistinguishable from their control lit- termates. HDAC1 and HDAC2 can compensate for each other in other systems 11,18 . Thus, we analyzed Dhh Cre Hdac1-Hdac2 double homozygous knockout (H1/2 −/− ) mice. H1/2 −/− mice showed tremor and reduced hind limb mobility, and died around P17. Structural analyses revealed a partial axonal sort- ing delay at P1 (Fig. 1a). At P5, most axons in control mice (Dhh Cre− ) were myelinated, whereas many H1/2 −/− axons were sorted in a one- to-one relationship with Schwann cells but remained mostly unmy- elinated (Fig. 1b). No myelin was found at P10 or P16 (data not shown and Supplementary Fig. 2a,b). At P5, many H1/2 −/− Schwann cells showed signs of damage such as cytoplasm vacuolization and fragmentation, and at P10 empty basal lamina remnants were com- monly found around axons (Fig. 1c). Massive apoptosis occurred in H1/2 −/− nerves, with onset at P2 (Fig. 1d and Supplementary Table 1), resulting in virtual absence of Schwann cells at P16 (Fig. 1e and Supplementary Fig. 2a,b). Apoptotic cells were positive for the Schwann cell markers 19 GFAP, S100 (Supplementary Fig. 3a) and Oct-6 (Supplementary Fig. 3b). At P16, nerves were exclusively composed of aberrant mini-fascicles of axons (Supplementary Fig. 2a,b), surrounded by cells with perineurial-like characteristics such as prominent caveolae (data not shown) and expression of the tight junction proteins ZO-1 (ref. 20) and Claudin-1 that stain perineu- rial cells in control nerves (Supplementary Fig. 2c). In the absence of 1 Institute of Cell Biology, Department of Biology, ETH Zurich, Zurich, Switzerland. 2 Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. 3 Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland. 4 These authors contributed equally to this work. Correspondence should be addressed to C.J. (claire.jacob@cell.biol.ethz.ch) or U.S. (usuter@cell.biol.ethz.ch). Received 10 September 2010; accepted 24 January 2011; published online 20 March 2011; doi:10.1038/nn.2762 HDAC1 and HDAC2 control the transcriptional program of myelination and the survival of Schwann cells Claire Jacob 1 , Carlos N Christen 1,4 , Jorge A Pereira 1,4 , Christian Somandin 1,4 , Arianna Baggiolini 1 , Pirmin Lötscher 1 , Murat Özçelik 1 , Nicolas Tricaud 1 , Dies Meijer 2 , Teppei Yamaguchi 3 , Patrick Matthias 3 & Ueli Suter 1 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 -catenin. © 2011 Nature America, Inc. All rights reserved.