Abstract
After peripheral nerve injury, axons regenerate and become remyelinated by resident Schwann cells. However, myelin repair never results in the original myelin thickness, suggesting insufficient stimulation by neuronal growth factors. Upon testing this hypothesis, we found that axonal neuregulin-1 (NRG1) type III and, unexpectedly, also NRG1 type I restored normal myelination when overexpressed in transgenic mice. This led to the observation that Wallerian degeneration induced de novo NRG1 type I expression in Schwann cells themselves. Mutant mice lacking a functional Nrg1 gene in Schwann cells are fully myelinated but exhibit impaired remyelination in adult life. We suggest a model in which loss of axonal contact triggers denervated Schwann cells to transiently express NRG1 as an autocrine/paracrine signal that promotes Schwann cell differentiation and remyelination.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Axons / drug effects
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Axons / pathology
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Axons / ultrastructure
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Cell Proliferation / drug effects
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Cells, Cultured
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Culture Media, Conditioned / pharmacology
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Demyelinating Diseases / etiology
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Demyelinating Diseases / metabolism*
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Disease Models, Animal
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Early Growth Response Protein 2 / metabolism
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Electric Stimulation
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Enzyme Inhibitors / pharmacology
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Evoked Potentials, Motor / drug effects
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Evoked Potentials, Motor / physiology
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Ganglia, Spinal / cytology
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Gene Expression Regulation / genetics
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Hedgehog Proteins / genetics
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Ki-67 Antigen / metabolism
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Locomotion / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microscopy, Electron, Transmission
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Myelin Basic Protein / metabolism
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Myelin P0 Protein / metabolism
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Myelin Sheath / metabolism
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Myelin Sheath / pathology
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NAV1.6 Voltage-Gated Sodium Channel / metabolism
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Neuregulin-1 / genetics
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Neuregulin-1 / metabolism*
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Neurons / chemistry
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Neurons / drug effects
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Neurons / metabolism
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Octamer Transcription Factor-6 / metabolism
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RNA, Messenger / metabolism
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Rats
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Recovery of Function / drug effects
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Recovery of Function / genetics*
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S100 Proteins / metabolism
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Schwann Cells / drug effects
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Schwann Cells / metabolism*
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Schwann Cells / ultrastructure
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Sciatic Nerve / cytology
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Sciatic Neuropathy / pathology*
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Sciatic Neuropathy / physiopathology
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Statistics, Nonparametric
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Time Factors
Substances
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Culture Media, Conditioned
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Early Growth Response Protein 2
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Egr2 protein, mouse
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Enzyme Inhibitors
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Hedgehog Proteins
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Ki-67 Antigen
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Mpz protein, mouse
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Myelin Basic Protein
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Myelin P0 Protein
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NAV1.6 Voltage-Gated Sodium Channel
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Neuregulin-1
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Nrg1 protein, mouse
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Pou3f1 protein, mouse
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RNA, Messenger
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S100 Proteins
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Scn8a protein, mouse
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Octamer Transcription Factor-6