ABSTRACT
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.
Subject(s)
Demyelinating Diseases/genetics , Neuregulin-1/genetics , Paracrine Communication , Schwann Cells/metabolism , Sural Nerve/metabolism , Animals , Animals, Genetically Modified , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/metabolism , Charcot-Marie-Tooth Disease/pathology , 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/metabolism , Neuritis, Autoimmune, Experimental/genetics , Neuritis, Autoimmune, Experimental/metabolism , Neuritis, Autoimmune, Experimental/pathology , Neuroglia/metabolism , Rats , Receptor, ErbB-2/metabolism , Schwann Cells/ultrastructure , Sciatic Nerve/injuries , Signal Transduction , Sural Nerve/ultrastructure , Tibial NerveABSTRACT
Michael W. Sereda was incorrectly associated with the Department of Cellular Neurophysiology, Hanover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany. The correct affiliations for Michael W. Sereda are Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany and Department of Clinical Neurophysiology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
ABSTRACT
Duplication of the gene encoding the peripheral myelin protein of 22 kDa (PMP22) underlies the most common inherited neuropathy, Charcot-Marie-Tooth 1A (CMT1A), a disease without a known cure. Although demyelination represents a characteristic feature, the clinical phenotype of CMT1A is determined by the degree of axonal loss, and patients suffer from progressive muscle weakness and impaired sensation. CMT1A disease manifests within the first two decades of life, and walking disabilities, foot deformities and electrophysiological abnormalities are already present in childhood. Here, we show in Pmp22-transgenic rodent models of CMT1A that Schwann cells acquire a persistent differentiation defect during early postnatal development, caused by imbalanced activity of the PI3K-Akt and the Mek-Erk signaling pathways. We demonstrate that enhanced PI3K-Akt signaling by axonally overexpressed neuregulin-1 (NRG1) type I drives diseased Schwann cells toward differentiation and preserves peripheral nerve axons. Notably, in a preclinical experimental therapy using a CMT1A rat model, when treatment is restricted to early postnatal development, soluble NRG1 effectively overcomes impaired peripheral nerve development and restores axon survival into adulthood. Our findings suggest a model in which Schwann cell differentiation within a limited time window is crucial for the long-term maintenance of axonal support.
