Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss.
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.
Chen
Suzhen
S
Division of Neuroscience, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Rio
Carlos
C
Ji
Ru-Rong
RR
Dikkes
Pieter
P
Coggeshall
Richard E
RE
Woolf
Clifford J
CJ
Corfas
Gabriel
G
D000123:Acetyltransferases; D048868:Adaptor Proteins, Signal Transducing; D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D001522:Behavior, Animal; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002452:Cell Count; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006023:Glycoproteins; D006720:Homozygote; D006930:Hyperalgesia / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D037102:Lectins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000648:ultrastructure; D009414:Nerve Growth Factors / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009475:Neurons, Afferent / Q000502:physiology*; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010147:Pain Measurement; D011930:Reaction Time; D066247:Receptor, ErbB-4; D020917:Receptor, trkA; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058477:Receptors, Purinergic P2X3; D012583:Schwann Cells / Q000502:physiology*; D012584:Sciatic Nerve / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism / Q000648:ultrastructure; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006023:Glycoproteins; D037102:Lectins; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D020890:Neuregulin-1; D016900:Neurofilament Proteins; D016761:Oncogene Proteins v-fos; C546407:P2RX3 protein, human; C546409:P2rx3 protein, mouse; C504649:PSIP1 protein, human; C504650:Psip1 protein, mouse; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; D015534:Trans-Activators; D014157:Transcription Factors; C473590:isolectin B4-binding glycoprotein, mouse; C051774:neurofilament protein H; D000123:Acetyltransferases; C111246:HTATIP2 protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D020917:Receptor, trkA; D001973:Bromodeoxyuridine