Glial growth factor/neuregulin inhibits Schwann cell myelination and induces demyelination

During development, neuregulin-1 promotes Schwann cell proliferation and su rvival; its role in later events of Schwann cell differentiation. including my elination, is poorly understood. Accordingly, we have examined the effe cts of neuregulin-1 on myelination in neuron-Schwann cell cocultures. Glial growth factor (GGF), a neuregulin-1 isoform, significantly inhibited myeli nation by preventing axonal segregation and ensheathment. Basal lamina form ation was not affected. Treatment of established myelinated cultures with G GF resulted in striking demyelination that frequently began at the paranode s and progressed to the internode, Demyelination was dose dependent and acc ompanied by dedifferentiation of Schwann cells to a promyelinating stage, a s evidenced by reexpression of the transcription factor suppressed cAMP-ind ucible POU; a significant proportion of cells with extensive demyelination also proliferated. Two other Schwann cell mitogens, fibroblast growth facto r-2 and transforming growth factor-p, inhibited myelination but did not cau se demyelination, suggesting this effect is specific to the neuregulins. Th e neuregulin receptor proteins, erbB2 and erbB3, are expressed on ensheathi ng and myelinating Schwann cells and rapidly phosphorylated with GGF treatm ent. 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 neu regulins, 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 condi tions.