Nestin-expressing neural progenitor cells (NPCs) have been isolated from hippocampus of brains and propagated with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). However, the underlying signaling mechanisms regulating NPC proliferation remain elusive. Here we showed that Neuregulin(31 (NRG), like bFGF, effectively promoted the proliferation of hippocampus-derived NPCs and maintained the progenitor states of NPCs. Activation of protein kinase C (PKC), a down-stream effector of phospholipase C (PLC), with 12-O-tetradecanoylphorboI- 13-acetate (TPA) mimicked the NRG-induced proliferation of NPCs. The synergic effect of TPA plus NRG on neurosphere growth further prompted us to find that NRG induced NPC propagation through PLC/PKC signaling pathway. ErbB4, an important functional receptor of NRG, had an interaction with PLCyi protein. In addition, inactivation of PLC pathway led to severe proliferative suppression of NPCs. Our study suggests that activation of PLC/PKC pathway may play an essential role in the NRG-induced proliferation of hippocampus-derived NPCs. Increasing evidences suggest that, after neuregulin (NRG) stimulation, ErbB4 undergoes a series of proteolysis, including y-secretase cleavage. The released ErB4 intracellular domain (EICD) is translocated into nucleus and has a transcriptional function. Although NRG-ErbB4 signaling mediates maturation of oligodendrocytes (OLs), the role of EICD and y-secretase in this process remain elusive. Here, we showed that NRG-ErbB4 interaction accumulated EICD in the nucleus and promoted the expression of myelin basic protein expression in OLs. Conversely, inhibitor of ErbB4 or y-secretase blocked the capacity of NRG. Nuclear accumulation of EICD did not influence maturation of neurons and astrocytes and early development of OLs. We also found that EICD translocation accorded a temporal pattern, consistent with the developmental gradient of hippocampus. Our data suggest that y-secretase activation and EICD nuclear translocation are required for OL maturation induced by NRG, and ErbB4 acts as a functional receptor depending on a new signaling cascade.