Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC, 20010, USA.
Neonatology Department, Children's National Hospital, Washington, DC, 20010, USA.
Nat Commun. 2022 Aug 15;13(1):4771. doi: 10.1038/s41467-022-32462-2.
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 OL 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 in a mouse model of 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 OLs were also observed in the white matter of preterm human infants. We show that Sirt2 interacts with p27/FoxO1, p21/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.
缺氧诱导的新生儿脑损伤导致少突胶质细胞（OL）成熟延迟，从而导致少突胶质化不足，并导致神经功能障碍。此前，我们将 Sirt1 鉴定为 OL 祖细胞（OPC）增殖对缺氧反应的关键调节因子。现在我们发现 Sirt2 是正常白质发育和缺氧模型中小鼠 OL 分化的关键促进因子。重要的是，我们发现缺氧会降低成熟 OL 中的 Sirt2 表达，而过表达 OPC 中的 Sirt2 可恢复成熟 OL 群体。在早产儿的白质中也观察到 Sirt2 OL 的数量减少。我们表明 Sirt2 与 p27/FoxO1、p21/Cdk4 和 Cdk5 途径相互作用，并且这些相互作用受缺氧影响而改变。此外，缺氧诱导 OPC 中 Sirt2 的核易位，其中它与几个基因组靶标结合。总的来说，这些结果表明 Sirt1 和 Sirt2 活性的平衡对于发育性少突胶质发生是必需的，并且这些蛋白代表了促进白质损伤后修复的潜在靶标。
