Ablation of the transcription factors E2F1-2 limits neuroinflammation and associated neurological deficits after contusive spinal cord injury.
Traumatic spinal cord injury (SCI) induces cell cycle activation (CCA) that contributes to secondary injury and related functional impairments such as motor deficits and hyperpathia. E2F1 and E2F2 are members of the activator sub-family of E2F transcription factors that play an important role in proliferating cells and in cell cycle-related neuronal death, but no comprehensive study have been performed in SCI to determine the relative importance of these factors. Here we examined the temporal distribution and cell-type specificity of E2F1 and E2F2 expression following mouse SCI, as well as the effects of genetic deletion of E2F1-2 on neuronal cell death, neuroinflammation and associated neurological dysfunction. SCI significantly increased E2F1 and E2F2 expression in active caspase-3(+) neurons/oligodendrocytes as well as in activated microglia/astrocytes. Injury-induced up-regulation of cell cycle-related genes and protein was significantly reduced by intrathecal injection of high specificity E2F decoy oligodeoxynucleotides against the E2F-binding site or in E2F1-2 null mice. Combined E2F1+2 siRNA treatment show greater neuroprotection in vivo than E2F1 or E2F2 single siRNA treatment. Knockout of both E2F1 and E2F2 genes (E2Fdko) significantly reduced neuronal death, neuroinflammation, and tissue damage, as well as limiting motor dysfunction and hyperpathia after SCI. Both CCA reduction and functional improvement in E2Fdko mice were greater than those in E2F2ko model. These studies demonstrate that SCI-induced activation of E2F1-2 mediates CCA, contributing to gliopathy and neuronal/tissue loss associated with motor impairments and post-traumatic hyperesthesia. Thus, E2F1-2 provide a therapeutic target for decreasing secondary tissue damage and promoting recovery of function after SCI.
a Department of Anesthesiology and Center for Shock ; Trauma and Anesthesiology Research (STAR); University of Maryland School of Medicine ; Baltimore , MD USA.|b Department of Anatomy and Neurobiology ; University of Maryland School of Medicine ; Baltimore , MD USA.
Junfang
J
Wu
a Department of Anesthesiology and Center for Shock ; Trauma and Anesthesiology Research (STAR); University of Maryland School of Medicine ; Baltimore , MD USA.
Boris
B
Sabirzhanov
a Department of Anesthesiology and Center for Shock ; Trauma and Anesthesiology Research (STAR); University of Maryland School of Medicine ; Baltimore , MD USA.|b Department of Anatomy and Neurobiology ; University of Maryland School of Medicine ; Baltimore , MD USA.
Bogdan A
BA
Stoica
a Department of Anesthesiology and Center for Shock ; Trauma and Anesthesiology Research (STAR); University of Maryland School of Medicine ; Baltimore , MD USA.|b Department of Anatomy and Neurobiology ; University of Maryland School of Medicine ; Baltimore , MD USA.
Marta M
MM
Lipinski
a Department of Anesthesiology and Center for Shock ; Trauma and Anesthesiology Research (STAR); University of Maryland School of Medicine ; Baltimore , MD USA.
Zaorui
Z
Zhao
a Department of Anesthesiology and Center for Shock ; Trauma and Anesthesiology Research (STAR); University of Maryland School of Medicine ; Baltimore , MD USA.
Shuxin
S
Zhao
a Department of Anesthesiology and Center for Shock ; Trauma and Anesthesiology Research (STAR); University of Maryland School of Medicine ; Baltimore , MD USA.
Nicole
N
Ward
a Department of Anesthesiology and Center for Shock ; Trauma and Anesthesiology Research (STAR); University of Maryland School of Medicine ; Baltimore , MD USA.
Dianer
D
Yang
a Department of Anesthesiology and Center for Shock ; Trauma and Anesthesiology Research (STAR); University of Maryland School of Medicine ; Baltimore , MD USA.|b Department of Anatomy and Neurobiology ; University of Maryland School of Medicine ; Baltimore , MD USA.
Alan I
AI
Faden
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050703:E2F2 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D055786:Gene Knockout Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor
E2F1; E2F2; astrocytes; cell cycle pathways; contusive spinal cord injury; inflammation; motor function; neuropathic pain; neuroprotection