NRG1 type I dependent autoparacrine stimulation of Schwann cells in onion bulbs of peripheral neuropathies

• Published in: Nature communications Vol. 10; no. 1; pp. 1467 - 17
• Main Authors: Fledrich, Robert, Akkermann, Dagmar, Schütza, Vlad, Abdelaal, Tamer A., Hermes, Doris, Schäffner, Erik, Soto-Bernardini, M. Clara, Götze, Tilmann, Klink, Axel, Kusch, Kathrin, Krueger, Martin, Kungl, Theresa, Frydrychowicz, Clara, Möbius, Wiebke, Brück, Wolfgang, Mueller, Wolf C., Bechmann, Ingo, Sereda, Michael W., Schwab, Markus H., Nave, Klaus-Armin, Stassart, Ruth M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14/28; 14/34; 38/32; 38/77; 42/41; 631/378/2596/3921; 64/60; 64/86; 692/617/375/430; 82/1; 82/79; 96; Adults; Animals; Animals, Genetically Modified; Biopsy; Bulbs; Charcot-Marie-Tooth disease; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - metabolism; Charcot-Marie-Tooth Disease - pathology; Demyelinating diseases; Demyelinating Diseases - genetics; Demyelinating Diseases - metabolism; Demyelinating Diseases - pathology; Demyelination; Diabetes Mellitus, Type 1 - complications; Diabetic Neuropathies - etiology; Diabetic Neuropathies - genetics; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - pathology; Disease; Disruption; Epidermal growth factor; ErbB-2 protein; Genotype & phenotype; Growth factors; Humanities and Social Sciences; Humans; MAP Kinase Signaling System; Mice; Mice, Transgenic; Microscopy, Electron; Motor Activity; multidisciplinary; Myelin Proteins - genetics; Nervous system; Neuregulin; Neuregulin 1; Neuregulin-1 - genetics; Neuregulin-1 - metabolism; Neuritis, Autoimmune, Experimental - genetics; Neuritis, Autoimmune, Experimental - metabolism; Neuritis, Autoimmune, Experimental - pathology; Neuroglia - metabolism; Neuropathology; Neurophysiology; Onions; Paracrine Communication; Paracrine signalling; Peripheral neuropathy; Proteins; Rats; Receptor, ErbB-2 - metabolism; Regeneration; Schwann cells; Schwann Cells - metabolism; Schwann Cells - ultrastructure; Sciatic Nerve - injuries; Science; Science (multidisciplinary); Signal Transduction; Sural Nerve - metabolism; Sural Nerve - ultrastructure; Tibial Nerve; Vegetables
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09385-6

In contrast to acute peripheral nerve injury, the molecular response of Schwann cells in chronic neuropathies remains poorly understood. Onion bulb structures are a pathological hallmark of demyelinating neuropathies, but the nature of these formations is unknown. Here, we show that Schwann cells induce the expression of Neuregulin-1 type I (NRG1-I), a paracrine growth factor, in various chronic demyelinating diseases. Genetic disruption of Schwann cell-derived NRG1 signalling in a mouse model of Charcot-Marie-Tooth Disease 1A (CMT1A), suppresses hypermyelination and the formation of onion bulbs. Transgenic overexpression of NRG1-I in Schwann cells on a wildtype background is sufficient to mediate an interaction between Schwann cells via an ErbB2 receptor-MEK/ERK signaling axis, which causes onion bulb formations and results in a peripheral neuropathy reminiscent of CMT1A. We suggest that diseased Schwann cells mount a regeneration program that is beneficial in acute nerve injury, but that overstimulation of Schwann cells in chronic neuropathies is detrimental. Onion bulbs are a hallmark of demyelinating peripheral neuropathies. Here the authors identify Neuregulin-1 type I expression in Schwann cells as an essential mechanism involved in the formation of these characteristic structures.