Pen-2 Negatively Regulates the Differentiation of Oligodendrocyte Precursor Cells into Astrocytes in the Central Nervous System

Mutations on gamma-secretase subunits are associated with neurologic diseases. Whereas the role of gamma-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 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 oligodendrocyte lineage-specific presenilin enhancer 2 (Pen-2) conditional KO 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 OPCsin the CNS in Pen-2 conditional KO mice. Mechanistic analysis reveals that deletion of Pen-2 inhibits the Notch signaling to upregulate signal transducer and activator of transcription 3, 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 signal transducer and activator of transcription 3 signaling.

Automated summary

Mutations on gamma-secretase subunits are linked to neurological diseases. While the role of gamma-secretase in neurogenesis is well-studied, its involvement in astrogliogenesis remains unclear. Recent evidence suggests that astrocytes can be derived from oligodendrocyte precursor cells (OPCs), but the mechanism controlling this differentiation is not fully understood.