title: Rit GTPase signaling promotes immature hippocampal neuronal survival.
abstract: The molecular mechanisms governing the spontaneous recovery seen following brain injury remain elusive, but recent studies indicate that injury-induced stimulation of hippocampal neurogenesis contributes to the repair process. The therapeutic potential of endogenous neurogenesis is tempered by the demonstration that traumatic brain injury (TBI) results in the selective death of adult-born immature neurons, compromising the cell population poised to compensate for trauma-induced neuronal loss. Here, we identify the Ras-related GTPase, Rit, as a critical player in the survival of immature hippocampal neurons following brain injury. While Rit knock-out (Rit(-/-)) did not alter hippocampal development, hippocampal neural cultures derived from Rit(-/-) mice display increased cell death and blunted MAPK cascade activation in response to oxidative stress, without affecting BDNF-dependent signaling. When compared with wild-type hippocampal cultures, Rit loss rendered immature (Dcx(+)) neurons susceptible to oxidative damage, without altering the survival of neural progenitor (Nestin(+)) cells. Oxidative stress is a major contributor to neuronal cell death following brain injury. Consistent with the enhanced vulnerability of cultured Rit(-/-) immature neurons, Rit(-/-) mice exhibited a significantly greater loss of adult-born immature neurons within the dentate gyrus after TBI. In addition, post-TBI neuronal remodeling was blunted. Together, these data identify a new and unexpected role for Rit in injury-induced neurogenesis, functioning as a selective survival mechanism for immature hippocampal neurons within the subgranular zone of the dentate gyrus following TBI.
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA.
authors: Weikang
authors: W
authors: Cai
authors: Shaun W
authors: SW
authors: Carlson
authors: Jennifer M
authors: JM
authors: Brelsfoard
authors: Catherine E
authors: CE
authors: Mannon
authors: Carole L
authors: CL
authors: Moncman
authors: Kathryn E
authors: KE
authors: Saatman
authors: Douglas A
authors: DA
authors: Andres
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism; D000089662:Doublecortin Protein; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; C472865:Rit1 protein, mouse; D018631:ras Proteins