Mutations on γ-secretase subunits are associated with neurological diseases. Whereas the role of γ-secretase in neurogenesis has been intensively studied, little is known about its role in astrogliogenesis. Recent evidence has demonstrated that astrocytes can be generated from oligodendrocyte (OL) precursor cells (OPCs). However, it is not well understood what mechanism may control OPCs to differentiate into astrocytes. To address the above questions, we generated two independent lines of OL lineage specific presenilin enhancer 2 ( Pen-2 ) conditional knockout (cKO) mice. Both male and female mice were used. Here we demonstrate that conditional inactivation of Pen-2 mediated by Olig1-Cre or NG2-CreERT2 causes enhanced generation of astrocytes. Lineage-tracing experiments indicate that abnormally generated astrocytes are derived from Cre-expressing OPCs in the central nervous system (CNS) in Pen-2 cKO mice. Mechanistic analysis reveals that deletion of Pen-2 inhibits the Notch signaling to up-regulate signa...