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The Journal of Neuroscience, November 26, 2008, 28(48):12901-12912; doi:10.1523/JNEUROSCI.4629-08.2008
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Development/Plasticity/Repair
Traumatic Brain Injury-Induced Hippocampal Neurogenesis Requires Activation of Early Nestin-Expressing Progenitors
Tzong-Shiue Yu,1,2 Gui Zhang,1,2 Daniel J. Liebl,3 andSteven G. Kernie1,2 Departments of 1Pediatrics and 2Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, and 3The Miami Project to Cure Paralysis and University of Miami School of Medicine, Miami, Florida 33136
Correspondence should be addressed to Steven G. Kernie, Department of Developmental Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9133. Email: Steven.Kernie{at}utsouthwestern.edu
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.
Key words: traumatic brain injury; hippocampus; dentate gyrus; neurogenesis; neuroprotection; neuronal progenitor cell
Received Sept. 24, 2008; accepted Oct. 17, 2008.
Correspondence should be addressed to Steven G. Kernie, Department of Developmental Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9133. Email: Steven.Kernie{at}utsouthwestern.edu
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