Hypertrophic Neuropathies and Malignant Peripheral Nerve Sheath Tumors in Transgenic Mice Overexpressing Glial Growth Factor β3 in Myelinating Schwann Cells

The neuregulin-1 (NRG-1) family of growth and differentiation factors exerts a variety of effects on Schwann cells and their precursors during nervous system development; however, NRG-1 effects on adult Schwann cells are poorly defined. Several lines of evidence suggest that NRG-1 actions on adult Schwann cells are distinct from those observed during development. To test this hypothesis, we generated transgenic mice overexpressing the NRG-1 isoform glial growth factor β3 (GGFβ3) in myelinating Schwann cells [protein zero (P 0 )GGFβ3 mice]. P 0 -GGFβ3 mice develop resting tremors, gait abnormalities, decreased hindlimb strength, and paralysis by ∼7 months of age. Sciatic nerves from these animals show a hypertrophic neuropathy characterized by demyelination, remyelination, and “onion bulb” formation. Development of this hypertrophic neuropathy is preceded by Schwann cell hyperplasia that is prominent in 1-month-old mice and present but decreased in 2- and 4-month-old animals. P 0 -GGFβ3 mice also develop peripheral ganglion-associated malignant peripheral nerve sheath tumors. Motor, sensory, and sympathetic ganglia from 1-, 2-, and 4-month-old P 0 -GGFβ3 mice uniformly contain intraganglionic, likely preneoplastic, Schwann cell proliferations. Examination of bromodeoxyuridine incorporation and caspase-3 activation in sciatic nerves and trigeminal ganglia indicates that Schwann cell hyperplasia in P 0 -GGFβ3 mice reflects increased proliferation rather than decreased apoptosis. These observations are consistent with the hypothesis that GGFβ3 induces proliferation of adult Schwann cells and demyelination of peripheral nerve axons. Furthermore, overexpression of this NRG-1 isoform frequently induces neoplastic Schwann cell proliferation within PNS ganglia, suggesting that NRG-1 may contribute to human Schwann cell neoplasia.