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

Nat Commun. 2019 Apr 1;10(1):1467. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / metabolism
  • Charcot-Marie-Tooth Disease / pathology
  • Demyelinating Diseases / genetics*
  • Demyelinating Diseases / metabolism
  • Demyelinating Diseases / pathology
  • Diabetes Mellitus, Type 1 / complications
  • Diabetic Neuropathies / etiology
  • Diabetic Neuropathies / genetics
  • Diabetic Neuropathies / metabolism
  • Diabetic Neuropathies / pathology
  • Humans
  • MAP Kinase Signaling System
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Motor Activity
  • Myelin Proteins / genetics
  • Neuregulin-1 / genetics*
  • Neuregulin-1 / metabolism
  • Neuritis, Autoimmune, Experimental / genetics
  • Neuritis, Autoimmune, Experimental / metabolism
  • Neuritis, Autoimmune, Experimental / pathology
  • Neuroglia / metabolism
  • Paracrine Communication*
  • Rats
  • Receptor, ErbB-2 / metabolism
  • Schwann Cells / metabolism*
  • Schwann Cells / ultrastructure
  • Sciatic Nerve / injuries
  • Signal Transduction
  • Sural Nerve / metabolism*
  • Sural Nerve / ultrastructure
  • Tibial Nerve


  • Myelin Proteins
  • NRG1 protein, human
  • Neuregulin-1
  • Nrg1 protein, mouse
  • Nrg1 protein, rat
  • PMP22 protein, human
  • Erbb2 protein, mouse
  • Receptor, ErbB-2