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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetyltransferases*
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Adaptor Proteins, Signal Transducing
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Aging
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Animals
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Animals, Newborn
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Axons / metabolism
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Axons / ultrastructure
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Behavior, Animal
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Blotting, Western
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Bromodeoxyuridine / metabolism
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Carrier Proteins / metabolism
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Cell Count
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Cell Death / genetics
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Cell Death / physiology*
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ErbB Receptors / genetics
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ErbB Receptors / physiology*
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Ganglia, Spinal / cytology
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Ganglia, Spinal / metabolism
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Gene Expression Regulation, Developmental*
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Glial Cell Line-Derived Neurotrophic Factor
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Glycoproteins*
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Homozygote
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Hyperalgesia / metabolism
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Immunohistochemistry
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In Situ Nick-End Labeling
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Lectins / metabolism
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Membrane Proteins / metabolism
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Mice
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Mice, Transgenic
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Microscopy, Electron
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Myelin Sheath / ultrastructure
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Nerve Growth Factors / metabolism
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Neuregulin-1 / metabolism
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Neurofilament Proteins / metabolism
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Neurons, Afferent / physiology*
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Oncogene Proteins v-fos / metabolism
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Pain Measurement
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Reaction Time
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Receptor, ErbB-4
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Receptor, trkA*
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Receptors, Purinergic P2 / metabolism
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Receptors, Purinergic P2X3
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Schwann Cells / physiology*
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Sciatic Nerve / metabolism
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Sciatic Nerve / ultrastructure
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Spinal Cord / metabolism
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Spinal Cord / ultrastructure
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Trans-Activators / metabolism
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Transcription Factors / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Gdnf protein, mouse
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Glial Cell Line-Derived Neurotrophic Factor
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Glycoproteins
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Lectins
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Membrane Proteins
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Nerve Growth Factors
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Neuregulin-1
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Neurofilament Proteins
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Oncogene Proteins v-fos
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P2RX3 protein, human
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P2rx3 protein, mouse
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PSIP1 protein, human
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Psip1 protein, mouse
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Receptors, Purinergic P2
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Receptors, Purinergic P2X3
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Trans-Activators
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Transcription Factors
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isolectin B4-binding glycoprotein, mouse
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neurofilament protein H
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Acetyltransferases
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HTATIP2 protein, human
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ERBB4 protein, human
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ErbB Receptors
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Erbb4 protein, mouse
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Receptor, ErbB-4
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Receptor, trkA
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Bromodeoxyuridine