Pen-2 negatively regulates the differentiation of oligodendrocyte precursor cells into astrocytes in the central nervous system.

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 signal transducer and activator of transcription 3 (Stat3), which triggers activation of GFAP to promote astrocyte differentiation. Together, these novel findings indicate that Pen-2 regulates the specification of astrocytes from OPCs through the Stat3 signaling.SIGNIFICANCE STATEMENT:Astrocytes and oligodendrocyte (OLs) play critical roles in the brain. Recent evidence has demonstrated that astrocytes can be generated from OL precursor cells (OPCs). However, it remains poorly understood what mechanism governs the differentiation of OPCs into astrocytes. In this study, we took advantage of OL lineage cells specific presenilin enhancer 2 (Pen-2) conditional knockout (cKO) mice. We show that deletion of Pen-2 leads to dramatically enhanced astrocyte differentiation from OPCs in the central nervous system. Mechanistic analysis reveals that deletion of Pen-2 inhibits Hes1 and activates Stat3 to trigger GFAP activation which promotes astrocyte differentiation. Overall, this study identifies a novel function of Pen-2 in astrogliogenesis from OPCs.