title: Delaying histone deacetylase response to injury accelerates conversion into repair Schwann cells and nerve regeneration.
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.
authors.affiliation: Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
authors.forename: Valérie
authors.initials: V
authors.lastname: Brügger
authors.affiliation: Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
authors.forename: Mert
authors.initials: M
authors.lastname: Duman
authors.affiliation: Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
authors.forename: Maëlle
authors.initials: M
authors.lastname: Bochud
authors.affiliation: Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Münger
authors.affiliation: Proteomics and Mass Spectrometry Core Facility, Department of Clinical Research, University of Bern, Freiburgstrasse 15, 3010 Bern, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Heller
authors.affiliation: Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ruff
authors.affiliation: Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
authors.forename: Claire
authors.initials: C
authors.lastname: Jacob
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology*; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009416:Nerve Regeneration / Q000187:drug effects* / Q000235:genetics; D000072041:PAX3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D059348:Peripheral Nerve Injuries / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D020127:Recovery of Function / Q000187:drug effects; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D051767:Early Growth Response Protein 2; D056572:Histone Deacetylase Inhibitors; D000072041:PAX3 Transcription Factor; D011743:Pyrimidines; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors; C068686:Pax3 protein, mouse; C523184:mocetinostat; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2