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Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss

Nature Neuroscience volume 6, pages 1186–1193 (2003)Cite this article

Abstract

Here we studied the role of signaling through ErbB-family receptors in interactions between unmyelinated axons and non-myelinating Schwann cells in adult nerves. We generated transgenic mice that postnatally express a dominant-negative ErbB receptor in non-myelinating but not in myelinating Schwann cells. These mutant mice present a progressive peripheral neuropathy characterized by extensive Schwann cell proliferation and death, loss of unmyelinated axons and marked heat and cold pain insensitivity. At later stages, C-fiber sensory neurons die by apoptosis, a process that may result from reduced GDNF (glial cell line–derived neurotrophic factor) expression in the sciatic nerve. Neuregulin 1 (NRG1)-ErbB signaling mediates, therefore, reciprocal interactions between non-myelinating Schwann cells and unmyelinated sensory neuron axons that are critical for Schwann cell and C-fiber sensory neuron survival. This study provides new insights into ErbB signaling in adult Schwann cells, the contribution of non-myelinating Schwann cells in maintaining trophic support of sensory neurons, and the possible role of disrupted ErbB signaling in peripheral sensory neuropathies.

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Figure 1: Time course and pattern of DN-ErbB expression in the postnatal sciatic nerve.
Figure 2: Death and proliferation of non-myelinating Schwann cells in transgenic mice.
Figure 3: DN-ErbB4 mice show a progressive impairment in responses to noxious thermal but not mechanical stimuli.
Figure 4: The number of Fos-immunoreactive nuclei in the ipsilateral lumbar dorsal horn in response to heat and capsaicin stimuli is reduced in DN-ErbB4 mice.
Figure 5: Disorganization of Remak bundles and loss of unmyelinated axons in DN-ErbB4 mice.
Figure 6: Sensory neuron loss in dorsal root ganglion (DRG) of DN-ErbB4 mice.
Figure 7: Decreased levels of GDNF protein in sciatic nerves of DN-ErbB4 mice.

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Acknowledgements

Supported by National Institutes of Health grants: NINDS R01 NS35884 (G.C.), NIDCD R01 DC04820 (G.C.), NS40698 (R.R.J.), NS38253 (C.J.W.) and NS39518 (C.J.W.). Also supported by the EJLB Foundation (G.C.) and a Mental Retardation Research Center grant NIH P30-HD 18655 (G.C.). We thank N. Akhtar for technical assistance, B. Patten for comments, K. Stankovic for help with some experiments and S. Ito and the Harvard Medical School EM facility for their assistance with EM.

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Author notes

  1. Carlos Rio

    Present address: DIATER, Soledad 37, 2830 San Martin de la Vega, Madrid, Spain

  2. Suzhen Chen and Carlos Rio: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Neuroscience, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Suzhen Chen, Carlos Rio, Pieter Dikkes & Gabriel Corfas

  2. Department of Anesthesia and Critical Care, Neural Plasticity Research Group, Massachusetts General Hospital and Harvard Medical School, Boston, 02129, Massachusetts, USA

    Ru-Rong Ji & Clifford J Woolf

  3. Department of Anatomy and Neuroscience, University of Texas Medical Branch, Galveston, 77555-1069, Texas, USA

    Richard E Coggeshall

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Correspondence to Gabriel Corfas.

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Chen, S., Rio, C., Ji, RR. et al. Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss. Nat Neurosci 6, 1186–1193 (2003). https://doi.org/10.1038/nn1139

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