title: Evidence that nucleocytoplasmic Olig2 translocation mediates brain-injury-induced differentiation of glial precursors to astrocytes.
abstract: The mechanisms by which neural and glial progenitor cells in the adult brain respond to tissue injury are unknown. We studied the responses of these cells to stab wound injury in rats and in two transgenic mouse models in which Y/GFP is driven either by Sox2 (a neural stem cell marker) or by Talpha-1 (which marks newly born neurons). The response of neural progenitors was low in all nonneurogenic regions, and no neurogenesis occurred at the injury site. Glial progenitors expressing Olig2 and NG2 showed the greatest response. The appearance of these progenitors preceded the appearance of reactive astrocytes. Surprisingly, we found evidence of the translocation of the transcription factor Olig2 into cytoplasm in the first week after injury, a mechanism that is known to mediate the differentiation of astrocytes during brain development. Translocation of Olig2, down-regulation of NG2, and increased glial fibrillary acidic protein expression were recapitulated in vitro after exposure of glial progenitors to serum components or bone morphogentic protein by up-regulation of Notch-1. The glial differentiation and Olig2 translocation could be blocked by inhibition of Notch-1 with the gamma-secretase inhibitor DAPT. Together, these data indicate that the prompt maturation of numerous Olig2(+) glial progenitors to astrocytes underlies the repair process after a traumatic injury. In contrast, neural stem cells and neuronal progenitor cells appear to play only a minor role in the injured adult CNS.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA. magnust@mail.nih.gov
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.forename: Turhan
authors.initials: T
authors.lastname: Coksaygan
authors.forename: Thomas
authors.initials: T
authors.lastname: Korn
authors.forename: Haipeng
authors.initials: H
authors.lastname: Xue
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Mughal
authors.forename: D Mark
authors.initials: DM
authors.lastname: Eckley
authors.forename: Sung-Chun
authors.initials: SC
authors.lastname: Tang
authors.forename: Louis
authors.initials: L
authors.lastname: Detolla
authors.forename: Mahendra S
authors.initials: MS
authors.lastname: Rao
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cassiani-Ingoni
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001692:Biological Transport; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D024002:HMGB Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009457:Neuroglia / Q000473:pathology*; D000076104:Oligodendrocyte Transcription Factor 2; D051381:Rats; D011916:Rats, Inbred F344; D051881:Receptor, Notch1 / Q000378:metabolism; D055748:SOXB1 Transcription Factors; D013234:Stem Cells / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism; D014951:Wounds, Stab / Q000378:metabolism / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D024002:HMGB Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D051881:Receptor, Notch1; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; C512773:Olig2 protein, mouse; C522729:Olig2 protein, rat; C527783:Sox2 protein, mouse; C527784:Sox2 protein, rat