Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury
| Autor: | Teresa S. Hawley, Juan Cabrera-Luque, Vittorio Gallo, Beata Jablonska, Marcin Gierdalski, Li-Jin Chew, David H. Rowitch, Tracy J. Yuen, Arturo Lichauco, Mackenzie Catron |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Science Cell General Physics and Astronomy General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Mice Neural Stem Cells Sirtuin 1 medicine E2F1 Animals Progenitor cell Hypoxia Cells Cultured Progenitor Cell Proliferation Mice Knockout Gene knockdown Multidisciplinary biology Cyclin-dependent kinase 2 Cell Differentiation General Chemistry Anatomy Hypoxia-Inducible Factor 1 alpha Subunit White Matter Oligodendrocyte 3. Good health Cell biology Nerve Regeneration enzymes and coenzymes (carbohydrates) stomatognathic diseases 030104 developmental biology medicine.anatomical_structure nervous system Animals Newborn Brain Injuries biology.protein Female RNA Interference Histone deacetylase biological phenomena cell phenomena and immunity Neuroglia hormones hormone substitutes and hormone antagonists |
| Zdroj: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-16 (2016) |
| ISSN: | 2041-1723 |
| Popis: | Regenerative processes in brain pathologies require the production of distinct neural cell populations from endogenous progenitor cells. We have previously demonstrated that oligodendrocyte progenitor cell (OPC) proliferation is crucial for oligodendrocyte (OL) regeneration in a mouse model of neonatal hypoxia (HX) that reproduces diffuse white matter injury (DWMI) of premature infants. Here we identify the histone deacetylase Sirt1 as a Cdk2 regulator in OPC proliferation and response to HX. HX enhances Sirt1 and Sirt1/Cdk2 complex formation through HIF1α activation. Sirt1 deacetylates retinoblastoma (Rb) in the Rb/E2F1 complex, leading to dissociation of E2F1 and enhanced OPC proliferation. Sirt1 knockdown in culture and its targeted ablation in vivo suppresses basal and HX-induced OPC proliferation. Inhibition of Sirt1 also promotes OPC differentiation after HX. Our results indicate that Sirt1 is an essential regulator of OPC proliferation and OL regeneration after neonatal brain injury. Therefore, enhancing Sirt1 activity may promote OL recovery after DWMI. Oligodendrocyte progenitor cell (OPC) proliferation is crucial for regeneration after hypoxic lesions in mice, a model of diffuse white matter injury of premature infants. Here, the authors show that the histone deacetylase Sirt1 is a Cdk2-dependent mediator of OPC proliferation and OPC response to hypoxia. |
| Databáze: | OpenAIRE |
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