title: HDAC1/2-Dependent P0 Expression Maintains Paranodal and Nodal Integrity Independently of Myelin Stability through Interactions with Neurofascins.
abstract: The pathogenesis of peripheral neuropathies in adults is linked to maintenance mechanisms that are not well understood. Here, we elucidate a novel critical maintenance mechanism for Schwann cell (SC)-axon interaction. Using mouse genetics, ablation of the transcriptional regulators histone deacetylases 1 and 2 (HDAC1/2) in adult SCs severely affected paranodal and nodal integrity and led to demyelination/remyelination. Expression levels of the HDAC1/2 target gene myelin protein zero (P0) were reduced by half, accompanied by altered localization and stability of neurofascin (NFasc)155, NFasc186, and loss of Caspr and septate-like junctions. We identify P0 as a novel binding partner of NFasc155 and NFasc186, both in vivo and by in vitro adhesion assay. Furthermore, we demonstrate that HDAC1/2-dependent P0 expression is crucial for the maintenance of paranodal/nodal integrity and axonal function through interaction of P0 with neurofascins. In addition, we show that the latter mechanism is impaired by some P0 mutations that lead to late onset Charcot-Marie-Tooth disease.
authors.affiliation: Department of Biology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Valérie
authors.initials: V
authors.lastname: Brügger
authors.affiliation: Department of Biology, University of Fribourg, Fribourg, Switzerland; Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Engler
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Pereira
authors.affiliation: Department of Biology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ruff
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Horn
authors.affiliation: Department of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Welzl
authors.affiliation: Department of Biology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Münger
authors.affiliation: Department of Biology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Adrien
authors.initials: A
authors.lastname: Vaquié
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Páris N M
authors.initials: PN
authors.lastname: Sidiropoulos
authors.affiliation: Department of Biology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Boris
authors.initials: B
authors.lastname: Egger
authors.affiliation: Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Yotovski
authors.affiliation: Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
authors.forename: Luis
authors.initials: L
authors.lastname: Filgueira
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Somandin
authors.affiliation: Department of Materials, Laboratory for Biologically Oriented Materials, ETH Zurich, Zurich, Switzerland.
authors.forename: Tessa C
authors.initials: TC
authors.lastname: Lühmann
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Antonio
authors.affiliation: FMI for Biomedical Research, Novartis Research Foundation, Basel, Switzerland.
authors.forename: Teppei
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: FMI for Biomedical Research, Novartis Research Foundation, Basel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthias
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.affiliation: Department of Biology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Claire
authors.initials: C
authors.lastname: Jacob
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000201:enzymology / Q000235:genetics*; D055786:Gene Knockout Techniques; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006801:Humans; D051379:Mice; D018993:Myelin P0 Protein / Q000235:genetics*; D009186:Myelin Sheath / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; C491322:Cntnap1 protein, mouse; C560547:MPZ protein, human; C560546:Mpz protein, mouse; D018993:Myelin P0 Protein; D009414:Nerve Growth Factors; C504593:Nfasc protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2