Neuregulin 1 type III reduces severity in a mouse model of Congenital Hypomyelinating Neuropathy

Sophie, B.; Ornaghi, F.; Shackleford, G.; 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.-A.; Fratta, P.; Poitelon, Y.; D'Antonio, M.; Feltri, M. L.; Wrabetz, L.

doi:10.1101/386748

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bioRxiv · 10.1101/386748

Neuregulin 1 type III reduces severity in a mouse model of Congenital Hypomyelinating Neuropathy

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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 type III regulate Schwann cell fate and myelination. Here we ask if modulating neuregulin 1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we rescued the myelination defects by early overexpression of neuregulin 1 type III. Surprisingly, the rescue 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 (Pmp2) and oligodendrocyte myelin glycoprotein (Omg). 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 neuregulin 1 type III signaling has beneficial effects and restores myelination defects during development in a model of CHN.\n\n\n\nO_TBL View this table:\norg.highwire.dtl.DTLVardef@103281aorg.highwire.dtl.DTLVardef@3dc68eorg.highwire.dtl.DTLVardef@1b6c5feorg.highwire.dtl.DTLVardef@80e419org.highwire.dtl.DTLVardef@1ff2591_HPS_FORMAT_FIGEXP M_TBL C_TBL

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Sophie, B., Ornaghi, F., Shackleford, G., 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.-A., Fratta, P., Poitelon, Y., D'Antonio, M., Feltri, M. L., Wrabetz, L.. 2018-08-07. Neuregulin 1 type III reduces severity in a mouse model of Congenital Hypomyelinating Neuropathy. https://doi.org/10.1101/386748

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