Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury

Beata Jablonska (), Marcin Gierdalski, Li-Jin Chew, Teresa Hawley, Mackenzie Catron, Arturo Lichauco, Juan Cabrera-Luque, Tracy Yuen, David Rowitch and Vittorio Gallo ()
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Beata Jablonska: Center for Neuroscience Research, Children’s National Medical Center
Marcin Gierdalski: Children’s National Medical Center
Li-Jin Chew: Center for Neuroscience Research, Children’s National Medical Center
Teresa Hawley: Flow Cytometry Core Facility, George Washington University
Mackenzie Catron: Center for Neuroscience Research, Children’s National Medical Center
Arturo Lichauco: Center for Neuroscience Research, Children’s National Medical Center
Juan Cabrera-Luque: Center for Genetic Medicine, Children’s National Medical Center
Tracy Yuen: Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco
David Rowitch: Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco
Vittorio Gallo: Center for Neuroscience Research, Children’s National Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13866

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