γ-Secretase controls the specification of astrocytes from oligodendrocyte precursor cells via Stat3

Oligodendrocytes (OLs) and astrocytes play critical roles in a variety of brain functions. OL precursor cells (OPCs) are known to give rise to OLs as well as astrocytes. However, little is known about the mechanism by which OPCs determine their specification choice for OLs versus astrocytes in the central nervous system (CNS). Here we show that genetic inhibition of γ-secretase in OPCs reduces OL differentiation but enhances astrocyte specification. Mechanistic analysis reveals that inhibition of γ-secretase results in decreased levels of Hes1, and that Hes1 down-regulates the expression of signal transducer and activator of transcription3 (Stat3) via binding to specific regions of its promoter. We demonstrate that conditional inactivation of Stat3 in OL lineages restores the number of astrocytes in γ-secretase mutant mice. In summary, this study identifies a key mechanism which controls OPC9s specification choice for OL versus astrocyte during postnatal development. This γ-secretase-dependent machinery may be essential for the CNS to maintain the population balance between OLs and astrocytes.