GGF/neuregulin induces a phenotypic reversion of oligodendrocytes

We have previously shown that glial growth factor (GGF), a member of the neuregulin (NRG) family of growth factors, isa mitogen and survival factor for oligodendrocyte progenitors in cell culture and blocks their differentiation at the pro-oligodendrocyte stage (P. D. Canoll et al., 1996, Neuron 17, 229-243). We now show that GGF is able to induce differentiated oligodendrocytes to undergo a phenotypic reversion characterized by loss of MBP expression, reexpression of the intermediate filament protein nestin, reorganization of the actin cytoskeleton, and a dramatic reduction in the number of processes per cell. TUNEL analysis demonstrates that GGF is not cytotoxic for mature oligodendrocytes, but rather enhances their survival. GGF also induces the rapid activation of the PI 3-kinase and MAP kinase signaling pathways. These results further support a role for the NRGs in promoting the proliferation and survival of and inhibiting the differentiation of cells in the oligodendrocyte lineage and demonstrate that oligodendrocytes that differentiate in culture retain a substantial degree of phenotypic plasticity.