Akt Regulates Sox10 Expression to Control Oligodendrocyte Differentiation via Phosphorylating FoxO1.

Sox10 is a well known factor to control oligodendrocyte (OL) differentiation, and its expression is regulated by Olig2. As an important protein kinase, Akt has been implicated in diseases with white matter abnormalities. To study whether and how Akt may regulate OL development, we generated OL lineage cell-specific Akt1/Akt2/Akt3 triple conditional knock-out (Akt cTKO) mice. Both male and female mice were used. These mutants exhibit a complete loss of mature OLs and unchanged apoptotic cell death in the CNS. We show that the deletion of Akt three isoforms causes downregulation of Sox10 and decreased levels of phosphorylated FoxO1 in the brain. In vitro analysis reveals that the expression of FoxO1 with mutations on phosphorylation sites for Akt significantly represses the Sox10 promoter activity, suggesting that phosphorylation of FoxO1 by Akt is important for Sox10 expression. We further demonstrate that mutant FoxO1 without Akt phosphorylation epitopes is enriched in the Sox10 promoter. Together, this study identifies a novel FoxO1 phosphorylation-dependent mechanism for Sox10 expression and OL differentiation.SIGNIFICANCE STATEMENT Dysfunction of Akt is associated with white matter diseases including the agenesis of the corpus callosum. However, it remains unknown whether Akt plays an important role in oligodendrocyte differentiation. To address this question, we generated oligodendrocyte lineage cell-specific Akt1/Akt2/Akt3 triple-conditional knock-out mice. Akt mutants exhibit deficient white matter development, loss of mature oligodendrocytes, absence of myelination, and unchanged apoptotic cell death in the CNS. We demonstrate that deletion of Akt three isoforms leads to downregulation of Sox10, and that phosphorylation of FoxO1 by Akt is critical for Sox10 expression. Together, these findings reveal a novel mechanism to regulate Sox10 expression. This study may provide insights into molecular mechanisms for neurodevelopmental diseases caused by dysfunction of protein kinases.

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 neurologic 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 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 OPCs in 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.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 KO mice. We show that deletion of Pen-2 leads to dramatically enhanced astrocyte differentiation from OPCs in the CNS. Mechanistic analysis reveals that deletion of Pen-2 inhibits Hes1 and activates signal transducer and activator of transcription 3 to trigger GFAP activation which promotes astrocyte differentiation. Overall, this study identifies a novel function of Pen-2 in astrogliogenesis from OPCs.