Increasing evidences suggest that, after neuregulin (NRG) stimulation, ErbB4 undergoes a series of proteolysis, including gamma-secretase cleavage. The released ErbB4 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 gamma-secretase in this process remains 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 gamma-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 gamma-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.