title: Traumatic brain injury-induced hippocampal neurogenesis requires activation of early nestin-expressing progenitors.
abstract: It is becoming increasingly clear that brain injuries from a variety of causes stimulate neurogenesis within the hippocampus. It remains unclear, however, how robust this response may be and what primary cell types are involved. Here, using a controlled cortical impact model of traumatic brain injury on a previously characterized transgenic mouse line that expresses enhanced green fluorescent protein (eGFP) under the control of the nestin promoter, we demonstrate that it is the earliest type-1 quiescent progenitor cells that are induced to proliferate and migrate outside the subgranular layer of the dentate gyrus. This type-1 cell activation occurs at the same time that we observe adjacent but more differentiated doublecortin-expressing progenitors (type-2 cells) being eliminated. Also, although type-2 cells remain intact in the contralateral (uninjured) dentate gyrus, the type-1 cells there are also activated and result in increased numbers of the doublecortin-expressing type-2 cells. In addition, we have generated a novel mouse transgenic that expresses a modified version of the herpes simplex virus thymidine kinase along with eGFP that allows for the visualization and inducible ablation of early dividing progenitors by exposing them to ganciclovir. Using this transgenic in the context of traumatic brain injury, we demonstrate that these early progenitors are required for injury-induced remodeling to occur. This work suggests that injury-induced hippocampal remodeling following brain injury likely requires sustained activation of quiescent early progenitors.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.
authors.forename: Tzong-Shiue
authors.initials: TS
authors.lastname: Yu
authors.forename: Gui
authors.initials: G
authors.lastname: Zhang
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Liebl
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kernie
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism* / Q000503:physiopathology; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D015774:Ganciclovir / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009416:Nerve Regeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D064231:Nestin; D055495:Neurogenesis / Q000502:physiology*; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013937:Thymidine Kinase / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D000089622:Doublecortin Domain Proteins; D007381:Intermediate Filament Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D009479:Neuropeptides; D049452:Green Fluorescent Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir