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.


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*


  • 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

Grant support

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.