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

Author

Listed:
  • 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
    Howard Hughes Medical Institute, University of California, San Francisco
    Present address: Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK)

  • Vittorio Gallo

    (Center for Neuroscience Research, Children’s National Medical Center)

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.

Suggested Citation

  • Beata Jablonska & Marcin Gierdalski & Li-Jin Chew & Teresa Hawley & Mackenzie Catron & Arturo Lichauco & Juan Cabrera-Luque & Tracy Yuen & David Rowitch & Vittorio Gallo, 2016. "Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury," Nature Communications, Nature, vol. 7(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13866
    DOI: 10.1038/ncomms13866
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    Cited by:

    1. Beata Jablonska & Katrina L. Adams & Panagiotis Kratimenos & Zhen Li & Emma Strickland & Tarik F. Haydar & Katharina Kusch & Klaus-Armin Nave & Vittorio Gallo, 2022. "Sirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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