HDAC3 Regulates the Transition to the Homeostatic Myelinating Schwann Cell State
Laura H. Rosenberg,
Anne-Laure Cattin,
Xavier Fontana,
Elizabeth Harford-Wright,
Jemima J. Burden,
Ian J. White,
Jacob G. Smith,
Ilaria Napoli,
Victor Quereda,
Cristina Policarpi,
Jamie Freeman,
Robin Ketteler,
Antonella Riccio,
Alison C. Lloyd
Affiliations
Laura H. Rosenberg
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; CRUK Therapeutic Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK
Anne-Laure Cattin
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Xavier Fontana
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Elizabeth Harford-Wright
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Jemima J. Burden
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Ian J. White
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Jacob G. Smith
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Ilaria Napoli
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Victor Quereda
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
Cristina Policarpi
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Jamie Freeman
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; Horizon Discovery, 8100 Cambridge Research Park, Cambridge CB25 9TL, UK
Robin Ketteler
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Antonella Riccio
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
Alison C. Lloyd
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; UCL Cancer Institute, University College London, Gower Street, London WC1E 6BT, UK; Corresponding author
Summary: The formation of myelinating Schwann cells (mSCs) involves the remarkable biogenic process, which rapidly generates the myelin sheath. Once formed, the mSC transitions to a stable homeostatic state, with loss of this stability associated with neuropathies. The histone deacetylases histone deacetylase 1 (HDAC1) and HDAC2 are required for the myelination transcriptional program. Here, we show a distinct role for HDAC3, in that, while dispensable for the formation of mSCs, it is essential for the stability of the myelin sheath once formed—with loss resulting in progressive severe neuropathy in adulthood. This is associated with the prior failure to downregulate the biogenic program upon entering the homeostatic state leading to hypertrophy and hypermyelination of the mSCs, progressing to the development of severe myelination defects. Our results highlight distinct roles of HDAC1/2 and HDAC3 in controlling the differentiation and homeostatic states of a cell with broad implications for the understanding of this important cell-state transition. : The entry of differentiating cells into a homeostatic state is poorly understood. Here, Rosenberg et al. show that a switch between HDAC1/2 and HDAC3 is responsible for the entry of myelinating Schwann cells into homeostasis with HDAC3−/− Schwann cells myelinating normally but “overshooting,” resulting in severe neuropathies in adult mice. Keywords: homeostasis, HDACs, Schwann cells, peripheral nerve, neuropathy, biogenesis
