title: EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury.
abstract: Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, have a variety of roles in the developing and adult central nervous system that require direct cell-cell interactions; including regulating axon path finding, cell proliferation, migration and synaptic plasticity. Recently, we identified a novel pro-survival role for ephrins in the adult subventricular zone, where ephrinB3 blocks Eph-mediated cell death during adult neurogenesis. Here, we examined whether EphB3 mediates cell death in the adult forebrain following traumatic brain injury and whether ephrinB3 infusion could limit this effect. We show that EphB3 co-labels with microtubule-associated protein 2-positive neurons in the adult cortex and is closely associated with ephrinB3 ligand, which is reduced following controlled cortical impact (CCI) injury. In the complete absence of EphB3 (EphB3(-/-)), we observed reduced terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL), and functional improvements in motor deficits after CCI injury as compared with wild-type and ephrinB3(-/-) mice. We also demonstrated that EphB3 exhibits dependence receptor characteristics as it is cleaved by caspases and induces cell death, which is not observed in the presence of ephrinB3. Following trauma, infusion of pre-clustered ephrinB3-Fc molecules (eB3-Fc) into the contralateral ventricle reduced cortical infarct volume and TUNEL staining in the cortex, dentate gyrus and CA3 hippocampus of wild-type and ephrinB3(-/-) mice, but not EphB3(-/-) mice. Similarly, application of eB3-Fc improved motor functions after CCI injury. We conclude that EphB3 mediates cell death in the adult cortex through a novel dependence receptor-mediated cell death mechanism in the injured adult cortex and is attenuated following ephrinB3 stimulation.
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, 215 Duck Pond Drive, Blacksburg, VA 24061, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Theus
authors.affiliation: Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, R-48, Miami, FL 33136, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ricard
authors.affiliation: Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, R-48, Miami, FL 33136, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Glass
authors.affiliation: Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, R-48, Miami, FL 33136, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Travieso
authors.affiliation: Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, R-48, Miami, FL 33136, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Liebl
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D019610:Cytoprotection; D004195:Disease Models, Animal; D036389:Ephrin-B3 / Q000008:administration & dosage* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D036223:Receptor, EphB3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function; D045442:Rotarod Performance Test; D013997:Time Factors; D014162:Transfection
chemical_list: D036389:Ephrin-B3; D018696:Neuroprotective Agents; D036223:Receptor, EphB3