Sirt2 promotes white matter oligodendrogenesis during development and after neonatal hypoxia

Delayed oligodendrocyte (OL) maturation caused by hypoxia (Hx)-induced neonatal brain injury results in hypomyelination and leads to neurological disabilities. Previously, we characterized Sirt1 as a crucial regulator of oligodendrocyte progenitor cell (OPC) proliferation in response to Hx. We now identify Sirt2 as a critical promoter of OL differentiation during both normal white matter development and after Hx. Importantly, we find that Hx reduces Sirt2 expression in mature OLs and that Sirt2 overexpression in OPCs restores mature OL populations. Reduced numbers of Sirt2+ cells were also observed in the white matter of preterm infants. We show that Sirt2 interacts with p27Kip1/FoxO1, p21Cip1/Cdk4, and Cdk5 pathways, and that these interactions are altered by Hx. Furthermore, Hx induces nuclear translocation of Sirt2 in OPCs where it binds several genomic targets. Overall, these results indicate that a balance of Sirt1 and Sirt2 activity is required for developmental oligodendrogenesis, and that these proteins represent potential targets for promoting repair following white matter injury.