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Sirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia

Author

Listed:
  • Beata Jablonska

    (Children’s National Hospital)

  • Katrina L. Adams

    (Children’s National Hospital)

  • Panagiotis Kratimenos

    (Children’s National Hospital
    Children’s National Hospital)

  • Zhen Li

    (Children’s National Hospital)

  • Emma Strickland

    (Children’s National Hospital)

  • Tarik F. Haydar

    (Children’s National Hospital)

  • Katharina Kusch

    (Max Planck Institute of Experimental Medicine, Department of Neurogenetics)

  • Klaus-Armin Nave

    (Max Planck Institute of Experimental Medicine, Department of Neurogenetics)

  • Vittorio Gallo

    (Children’s National Hospital)

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+ OLs were also observed in the white matter of preterm human infants. We show that Sirt2 interacts with p27Kip1/FoxO1, p21Cip1/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.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32462-2
    DOI: 10.1038/s41467-022-32462-2
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    References listed on IDEAS

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    1. Thomas A. Forbes & Evan Z. Goldstein & Jeffrey L. Dupree & Beata Jablonska & Joseph Scafidi & Katrina L. Adams & Yuka Imamura & Kazue Hashimoto-Torii & Vittorio Gallo, 2020. "Environmental enrichment ameliorates perinatal brain injury and promotes functional white matter recovery," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    2. Shin-ichiro Imai & Christopher M. Armstrong & Matt Kaeberlein & Leonard Guarente, 2000. "Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase," Nature, Nature, vol. 403(6771), pages 795-800, February.
    3. 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.
    4. Katrina L. Adams & Giulia Riparini & Payal Banerjee & Marjolein Breur & Marianna Bugiani & Vittorio Gallo, 2020. "Endothelin-1 signaling maintains glial progenitor proliferation in the postnatal subventricular zone," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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