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The Journal of Neuroscience, August 13, 2003, 23(19):7269-7280

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Hypertrophic Neuropathies and Malignant Peripheral Nerve Sheath Tumors in Transgenic Mice Overexpressing Glial Growth Factor 3 in Myelinating Schwann Cells

Richard P. H. Huijbregts,¹ Kevin A. Roth,¹ Robert E. Schmidt,² and Steven L. Carroll¹

¹Division of Neuropathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, and ²Division of Neuropathology, Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

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 3 (GGF3) in myelinating Schwann cells [protein zero (P₀)GGF3 mice]. P₀-GGF3 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. P₀-GGF3 mice also develop peripheral ganglion-associated malignant peripheral nerve sheath tumors. Motor, sensory, and sympathetic ganglia from 1-, 2-, and 4-month-old P₀-GGF3 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 P₀-GGF3 mice reflects increased proliferation rather than decreased apoptosis. These observations are consistent with the hypothesis that GGF3 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.

Key words: Schwann cell; erbB receptor; schwannoma; neuropathy; neuregulin; glial growth factor

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Received Dec. 17, 2002; revised Jun. 3, 2003; accepted Jun. 6, 2003.

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