HDAC1/2-Dependent P0 Expression Maintains Paranodal and Nodal Integrity Independently of Myelin Stability through Interactions with Neurofascins

Valérie Brügger; Stefanie Engler; Jorge A Pereira; Sophie Ruff; Michael Horn; Hans Welzl; Emmanuelle Münger; Adrien Vaquié; Páris N M Sidiropoulos; Boris Egger; Peter Yotovski; Luis Filgueira; Christian Somandin; Tessa C Lühmann; Maurizio D'Antonio; Teppei Yamaguchi; Patrick Matthias; Ueli Suter; Claire Jacob

doi:10.1371/journal.pbio.1002258

HDAC1/2-Dependent P0 Expression Maintains Paranodal and Nodal Integrity Independently of Myelin Stability through Interactions with Neurofascins

PLoS Biol. 2015 Sep 25;13(9):e1002258. doi: 10.1371/journal.pbio.1002258. eCollection 2015.

Authors

Valérie Brügger¹, Stefanie Engler², Jorge A Pereira³, Sophie Ruff¹, Michael Horn³, Hans Welzl⁴, Emmanuelle Münger¹, Adrien Vaquié¹, Páris N M Sidiropoulos³, Boris Egger¹, Peter Yotovski⁵, Luis Filgueira⁵, Christian Somandin³, Tessa C Lühmann⁶, Maurizio D'Antonio⁷, Teppei Yamaguchi⁸, Patrick Matthias⁸, Ueli Suter³, Claire Jacob¹

Affiliations

¹ Department of Biology, University of Fribourg, Fribourg, Switzerland.
² Department of Biology, University of Fribourg, Fribourg, Switzerland; Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
³ Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
⁴ Department of Anatomy, University of Zurich, Zurich, Switzerland.
⁵ Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
⁶ Department of Materials, Laboratory for Biologically Oriented Materials, ETH Zurich, Zurich, Switzerland.
⁷ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milano, Italy.
⁸ FMI for Biomedical Research, Novartis Research Foundation, Basel, Switzerland.

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.

Publication types

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

MeSH terms

Animals
Cell Adhesion Molecules / metabolism*
Cell Adhesion Molecules, Neuronal / metabolism
Charcot-Marie-Tooth Disease / enzymology
Charcot-Marie-Tooth Disease / genetics*
Gene Knockout Techniques
Histone Deacetylase 1 / metabolism
Histone Deacetylase 2 / metabolism
Humans
Mice
Myelin P0 Protein / genetics*
Myelin Sheath / physiology*
Nerve Growth Factors / metabolism*

Substances

Cell Adhesion Molecules
Cell Adhesion Molecules, Neuronal
Cntnap1 protein, mouse
MPZ protein, human
Mpz protein, mouse
Myelin P0 Protein
Nerve Growth Factors
Nfasc protein, mouse
Histone Deacetylase 1
Histone Deacetylase 2

Associated data

Dryad/10.5061/dryad.8F1BT

Grants and funding

Swiss National Science Foundation (http://www.snf.ch/en/Pages/default.aspx) to CJ: SNSF Professorship no. PP00P3_139163 / 1), and to US: National Center for Competence in Research “Neural Plasticity and Repair” (http://www.nccr-neuro.ethz.ch/), and Novartis Research Foundation to PM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.