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Published online 19 March 2001. doi:10.1083/jcb.152.6.1289
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© The Rockefeller University Press, 0021-9525/2001//1289 $5.00
The Journal of Cell Biology, Volume 152, Number 6, , 2001 1289-1300

Original Article

Glial Growth Factor/Neuregulin Inhibits Schwann Cell Myelination and Induces Demyelination



George Zanazzia, Steven Einhebera, Richard Westreicha, Melanie-Jane Hannocksa, Debra Bedell-Hogand, Mark A. Marchionnid, and James L. Salzera,b,c

a Department of Cell Biology, New York University Medical Center, New York, New York 10016
b Department of Neurology, New York University Medical Center, New York, New York 10016
c The Kaplan Cancer Center, New York University Medical Center, New York, New York 10016
d Cambridge Neuroscience, Inc., Norwood, Massachusetts 02062
Department of Cell Biology, New York University Medical Center, 550 First Avenue, New York, NY 10016.(212) 263-0759(212) 263-5358

jim.salzer{at}med.nyu.edu

During development, neuregulin-1 promotes Schwann cell proliferation and survival; its role in later events of Schwann cell differentiation, including myelination, is poorly understood. Accordingly, we have examined the effects of neuregulin-1 on myelination in neuron-Schwann cell cocultures. Glial growth factor (GGF), a neuregulin-1 isoform, significantly inhibited myelination by preventing axonal segregation and ensheathment. Basal lamina formation was not affected. Treatment of established myelinated cultures with GGF resulted in striking demyelination that frequently began at the paranodes and progressed to the internode. Demyelination was dose dependent and accompanied by dedifferentiation of Schwann cells to a promyelinating stage, as evidenced by reexpression of the transcription factor suppressed cAMP-inducible POU; a significant proportion of cells with extensive demyelination also proliferated. Two other Schwann cell mitogens, fibroblast growth factor-2 and transforming growth factor-β, inhibited myelination but did not cause demyelination, suggesting this effect is specific to the neuregulins. The neuregulin receptor proteins, erbB2 and erbB3, are expressed on ensheathing and myelinating Schwann cells and rapidly phosphorylated with GGF treatment. GGF treatment of myelinating cultures also induced phosphorylation of phosphatidylinositol 3-kinase, mitogen-activated protein kinase, and a 120-kD protein. These results suggest that neuronal mitogens, including the neuregulins, may inhibit myelination during development and that activation of mitogen signaling pathways may contribute to the initial demyelination and subsequent Schwann cell proliferation observed in various pathologic conditions.

Key Words: Schwann cell • demyelination • mitogen • neuregulin • erbB

© 2001 The Rockefeller University Press

Abbreviations used in this paper: DRG, dorsal root ganglia; GGF, glial growth factor; MAP, mitogen-activated protein; MBP, myelin basic protein; PI, phosphatidylinositol; SCIP, suppressed cAMP-inducible POU.


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