Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy

Sophie Belin, Francesca Ornaghi, Ghjuvan'Ghjacumu Shackleford, Jie Wang, Cristina Scapin, Camila Lopez-Anido, Nicholas Silvestri, Neil Robertson, Courtney Williamson, Akihiro Ishii, Carla Taveggia, John Svaren, Rashmi Bansal, Markus H. Schwab, Klaus Nave, Pietro Fratta, Maurizio D'Antonio, Yannick Poitelon, M. Laura Feltri, Lawrence Wrabetz

Research output: Contribution to journalArticle

Abstract

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 (NRG1) type III regulate Schwann cell fate and myelination. Here we ask if modulating NRG1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we improved the myelination defects by early overexpression of NRG1 type III. Surprisingly, the improvement was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 and oligodendrocyte myelin glycoprotein. We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial NRG1 type III signaling has beneficial effects and improves myelination defects during development in a model of CHN.

Original languageEnglish
Pages (from-to)1260-1273
Number of pages14
JournalHuman Molecular Genetics
Volume28
Issue number8
DOIs
Publication statusPublished - Apr 15 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Belin, S., Ornaghi, F., Shackleford, GG., Wang, J., Scapin, C., Lopez-Anido, C., Silvestri, N., Robertson, N., Williamson, C., Ishii, A., Taveggia, C., Svaren, J., Bansal, R., Schwab, M. H., Nave, K., Fratta, P., D'Antonio, M., Poitelon, Y., Feltri, M. L., & Wrabetz, L. (2019). Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy. Human Molecular Genetics, 28(8), 1260-1273. https://doi.org/10.1093/hmg/ddy420