The intermediate filament (IF) protein nestin is a widely accepted molecular marker for neural progenitor cells (NPCs), but its function during neurogenesis remains largely unknown. We found that in embryonic cortical NPCs down-regulation of the expression of nestin, but not its co-polymer IF protein vimentin, resulted in a G1 cell-cycle arrest and a severe reduction in the generation of neurons. Furthermore, down-regulating nestin expression in cultured cortical NPCs markedly suppressed their colony-formation ability and blocked the elevation of the cyclin D1/E protein level in response to the treatment with bFGF. Interestingly, nestin down-regulation caused a marked suppression in the activation of the phosphoinositide 3-kinase (PI3K) pathway but not the mitogen-activated protein kinase (MAPK) pathway in these NPCs. Moreover, defects in the proliferation of cortical NPCs caused by nestin down-regulation could be prevented by up-regulating PI3K activity. Thus, nestin is essential for the proliferation of NPCs by promoting the activation of PI3K in response to mitogenic growth factors.
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