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.
Highlights
(Erk) signaling and a network of transcriptional regulators in adult Schwann cells[19], with a major role for the transcription factor cJUN20
Our findings identify the induction of the Neuregulin-1 type I (NRG1-I) isoform in Schwann cells as an integral part of a final common glial response in Charcot-Marie-Tooth Disease 1A (CMT1A) and most likely various other demyelinating polyneuropathies
While supernumerary Schwann cells in wild-type mice are normally eliminated within the first postnatal weeks, they persist in peripheral nerves of CMT1A mutants due to glial NRG1-Imediated survival functions
Summary
(Erk) signaling and a network of transcriptional regulators in adult Schwann cells[19], with a major role for the transcription factor cJUN20. When expressed on the axonal surface, the transmembrane NRG1 type III isoform controls virtually all steps of Schwann cell development and regulates myelin sheath thickness[21,23,24]. Wallerian degeneration of nerve fibers induces a de novo expression of the soluble Neuregulin-1 type 1 (NRG1-I) isoform in Schwann cells, a timely restricted signal that supports nerve repair and remyelination after acute nerve injury[29]. We demonstrate that Schwann cells in chronic demyelinating neuropathies induce expression of the paracrine NRG1-I isoform, which is required for disease pathogenesis in a CMT1A mouse model. We suggest a model according to which Schwann cells in peripheral nerve diseases mount a common NRG1-I-mediated regeneration program, which is beneficial after acute nerve injury but turns into a detrimental persistent response in chronic peripheral neuropathies, such as CMT1A
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