Delaying histone deacetylase response to injury accelerates conversion into repair Schwann cells and nerve regeneration

Valérie Brügger; Mert Duman; Maëlle Bochud; Emmanuelle Münger; Manfred Heller; Sophie Ruff; Claire Jacob

doi:10.1038/ncomms14272

Delaying histone deacetylase response to injury accelerates conversion into repair Schwann cells and nerve regeneration

Nat Commun. 2017 Jan 31:8:14272. doi: 10.1038/ncomms14272.

Authors

Valérie Brügger¹, Mert Duman¹, Maëlle Bochud¹, Emmanuelle Münger¹, Manfred Heller², Sophie Ruff¹, Claire Jacob¹

Affiliations

¹ Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
² Proteomics and Mass Spectrometry Core Facility, Department of Clinical Research, University of Bern, Freiburgstrasse 15, 3010 Bern, Switzerland.

Abstract

The peripheral nervous system (PNS) regenerates after injury. However, regeneration is often compromised in the case of large lesions, and the speed of axon reconnection to their target is critical for successful functional recovery. After injury, mature Schwann cells (SCs) convert into repair cells that foster axonal regrowth, and redifferentiate to rebuild myelin. These processes require the regulation of several transcription factors, but the driving mechanisms remain partially understood. Here we identify an early response to nerve injury controlled by histone deacetylase 2 (HDAC2), which coordinates the action of other chromatin-remodelling enzymes to induce the upregulation of Oct6, a key transcription factor for SC development. Inactivating this mechanism using mouse genetics allows earlier conversion into repair cells and leads to faster axonal regrowth, but impairs remyelination. Consistently, short-term HDAC1/2 inhibitor treatment early after lesion accelerates functional recovery and enhances regeneration, thereby identifying a new therapeutic strategy to improve PNS regeneration after lesion.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Axons / drug effects
Axons / metabolism
Benzamides / pharmacology*
Early Growth Response Protein 2 / genetics
Early Growth Response Protein 2 / metabolism
Gene Expression Regulation
Genes, Reporter
Histone Deacetylase 1 / antagonists & inhibitors
Histone Deacetylase 1 / deficiency
Histone Deacetylase 1 / genetics*
Histone Deacetylase 2 / antagonists & inhibitors
Histone Deacetylase 2 / deficiency
Histone Deacetylase 2 / genetics*
Histone Deacetylase Inhibitors / pharmacology*
JNK Mitogen-Activated Protein Kinases / genetics
JNK Mitogen-Activated Protein Kinases / metabolism
Luciferases / genetics
Luciferases / metabolism
Mice
Mice, Knockout
Nerve Regeneration / drug effects*
Nerve Regeneration / genetics
PAX3 Transcription Factor / genetics
PAX3 Transcription Factor / metabolism
Peripheral Nerve Injuries / drug therapy*
Peripheral Nerve Injuries / genetics
Peripheral Nerve Injuries / metabolism
Peripheral Nerve Injuries / pathology
Pyrimidines / pharmacology*
Recovery of Function / drug effects
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism
Schwann Cells / drug effects*
Schwann Cells / metabolism
Signal Transduction
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Benzamides
Early Growth Response Protein 2
Histone Deacetylase Inhibitors
PAX3 Transcription Factor
Pyrimidines
SOXB1 Transcription Factors
Sox2 protein, mouse
Transcription Factors
Pax3 protein, mouse
mocetinostat
Luciferases
JNK Mitogen-Activated Protein Kinases
Hdac1 protein, mouse
Hdac2 protein, mouse
Histone Deacetylase 1
Histone Deacetylase 2