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

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.

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure

“…We treated young CMT1A animals 6 to 7 days postnatal when peripheral nerve myelination is most active because a large amount of nerve defects and of motor impairments result from the alteration of the initial phase of nerve myelination. Indeed, early nerve defects and impairments already occur in young CMT1A rats [16,15,13]. This is consistent with the disease onset occurring in the first decade in 75% of CMT1A patients [40].…”

“…6a). A typical feature of CMT1A nerves is the shorter internodal distance [13,54]. Using CARS, we found that the number of nodes of Ranvier per fiber increased in CMT1A ctr.sh nerves compared to WT ctr.sh nerves ( Fig.…”

“…As a proof of concept, we chose a rat model of CMT1A in which mouse PMP22 is overexpressed [57]. This model closely mimics the human disease: immediately after peripheral nerve myelination begins, nerves show hypomyelination, shorter internodal lengths, deficit in large fibers, hypermyelination of small fibers, myelin sheath defects and demyelination [13,15,16]. We designed a therapeutic vector carrying both a small shRNA targeting mouse PMP22 mRNA under a U6 promoter and a CAG-eGFP reporter cassette.…”

Neuronal LXR Regulates Neuregulin-1 Expression and Sciatic Nerve-Associated Cell signaling

“…In the PNS, SC surrounds peripheral nerve axons with myelin membranes. Abnormal SC impairs PNS function 33,34,42 . During peripheral nerve development, SC differentiation and myelination critically depend on Nrg1, an axon-derived growth factor 26-28 .…”

“…During peripheral nerve development, SC differentiation and myelination critically depend on Nrg1, an axon-derived growth factor 26-28 . Nrg1 belongs to a family of transmembrane and secreted epidermal growth factor (EGF)-like growth factors, which activates ErbB receptor tyrosine kinases 42 . When expressed on the neuron axonal surface, the transmembrane Nrg1-type III isoform regulates SC development and myelin sheath thickness 28,43,44 .…”