Pen-2 regulates glial homeostasis by coordinating self-renewal and transdifferentiation programs in oligodendrocyte precursor cells.

Presenilin enhancer 2 (Pen-2) is implicated in neurological diseases characterized by glial dysregulation. To investigate whether oligodendrocytic γ-secretase activity is important for the maintenance of glial populations, we analyzed two conditional knockout (cKO) mouse models lacking Pen-2 or nicastrin. Both models exhibited similar expansions of oligodendrocyte precursor cells (OPCs) and astrocytes in the CNS. To test whether STAT3 mediates Pen-2-dependent glial homeostasis, we inactivated Stat3 in Pen-2 cKO mice. Intriguingly, STAT3 deficiency did not attenuate OPC expansion but normalized astrocyte numbers. We further demonstrated that Pen-2 represses Ascl1 expression via HES1 and that Ascl1 knockdown rescues the aberrant self-renewal capacity of Pen-2-deficient OPCs. Collectively, these results uncover a dual regulatory mechanism by which Pen-2 maintains glial homeostasis by (1) restraining OPC self-renewal through the HES1-ASCL1 axis and (2) suppressing OPC-to-astrocyte transdifferentiation in a STAT3-dependent manner. Our findings provide novel insights into glial abnormalities in PEN-2-linked neurological diseases.