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Hum Mol Genet. 2019 Apr 15;28(8):1260-1273. doi: 10.1093/hmg/ddy420.

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

Author information

1
Hunter James Kelly Research Institute, University at Buffalo, Buffalo, NY, USA.
2
Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
3
Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York, USA.
4
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
5
SR-TIGET, IRCCS, San Raffaele Scientific Institute, Milan, Italy.
6
Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
7
Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
8
Department of Neuroscience, University of Connecticut Medical School, Farmington, CT, USA.
9
Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
10
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
11
Department of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany.
12
Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, UK.

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.

PMID:
30535360
PMCID:
PMC6452193
[Available on 2020-04-15]
DOI:
10.1093/hmg/ddy420

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