Sirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35970992.
- Also identified by DOI 10.1038/s41467-022-32462-2 and PMC identifier 9378658.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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<sup>+</sup> OLs were also observed in the white matter of preterm human infants. We show that Sirt2 interacts with p27<sup>Kip1</sup>/FoxO1, p21<sup>Cip1</sup>/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.
Medical subject headings
- Hypoxia
- Oligodendroglia
- Sirtuin 2
- White Matter