title: Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury.
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.
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, 111 Michigan Avenue, Washington, District Of Columbia 20010, USA.
authors.forename: Beata
authors.initials: B
authors.lastname: Jablonska
authors.affiliation: Division of Cardiac Surgery, Children's National Medical Center, 111 Michigan Avenue, Washington, District Of Columbia 20010, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Gierdalski
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, 111 Michigan Avenue, Washington, District Of Columbia 20010, USA.
authors.forename: Li-Jin
authors.initials: LJ
authors.lastname: Chew
authors.affiliation: Flow Cytometry Core Facility, George Washington University, Washington, District Of Columbia 20052, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Hawley
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, 111 Michigan Avenue, Washington, District Of Columbia 20010, USA.
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Catron
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, 111 Michigan Avenue, Washington, District Of Columbia 20010, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Lichauco
authors.affiliation: Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Avenue, Washington, District Of Columbia 20010, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Cabrera-Luque
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Yuen
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, California 94143, USA.|Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rowitch
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, 111 Michigan Avenue, Washington, District Of Columbia 20010, USA.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Gallo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D000860:Hypoxia / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009416:Nerve Regeneration / Q000502:physiology*; D058953:Neural Stem Cells / Q000502:physiology*; D009457:Neuroglia; D034622:RNA Interference; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D066127:White Matter / Q000473:pathology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1