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 (WM) abnormalities. To study whether and how Akt may regulate OL development, we generated OL lineage cells-specific Akt1 / Akt2 / Akt3 triple conditional knockout ( Akt cTKO) mice. Both male and female mice were used. These mutants exhibit complete loss of mature OLs and unchanged apoptotic cell death in the central nervous system. We show that deletion of Akt three isoforms causes down-regulation of Sox10 and decreased levels of phosphorylated FoxO1 (pFoxO1) in the brain. In vitro analysis reveals that 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...