NRG1 type I dependent autoparacrine stimulation of Schwann cells in onion bulbs of peripheral neuropathies

In contrast to acute peripheral nerve injury, the molecular response of Schwann cellsin chronic neuropathies remains poorly understood. Onion bulbstructures are a pathological hallmark of demyelinating neuropathies, but the nature of these formations is unknown. Here, we show that Schwann cellsinduce the expression of Neuregulin-1type 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 Disease1A (CMT1A), suppresses hypermyelination and the formation of onion bulbs. Transgenic overexpression of NRG1-I in Schwann cellson a wildtype background is sufficient to mediate an interaction between Schwann cellsvia an ErbB2 receptor-MEK/ERK signaling axis, which causes onion bulbformations and results in a peripheral neuropathyreminiscent of CMT1A. We suggest that diseased Schwann cellsmount a regeneration program that is beneficial in acute nerve injury, but that overstimulation of Schwann cellsin chronic neuropathies is detrimental.