EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury

M. H. Theus, J. Ricard, S. J. Glass, L. G. Travieso, Daniel J Liebl

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Article numbere1207
JournalCell Death and Disease
Volume5
Issue number5
DOIs
StatePublished - Jan 1 2014

Fingerprint

EphB3 Receptor
Cell Death
Ephrins
Wounds and Injuries
Eph Family Receptors
Ligands
Parahippocampal Gyrus
Neuronal Plasticity
Microtubule-Associated Proteins
DNA Nucleotidylexotransferase
Lateral Ventricles
Neurogenesis
Dentate Gyrus
Caspases
Transferases
Prosencephalon
Cell Communication
Cell Movement
Axons
Central Nervous System

Keywords

  • Controlled cortical impact (CCI) injury
  • Eph receptors
  • Ephrins
  • Traumatic brain injury (TBI)

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Immunology
  • Cancer Research

Cite this

EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury. / Theus, M. H.; Ricard, J.; Glass, S. J.; Travieso, L. G.; Liebl, Daniel J.

In: Cell Death and Disease, Vol. 5, No. 5, e1207, 01.01.2014.

Research output: Contribution to journalArticle

@article{93ee3b999e5049b89c3dd9d2821ac818,
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.",
keywords = "Controlled cortical impact (CCI) injury, Eph receptors, Ephrins, Traumatic brain injury (TBI)",
author = "Theus, {M. H.} and J. Ricard and Glass, {S. J.} and Travieso, {L. G.} and Liebl, {Daniel J}",
year = "2014",
month = "1",
day = "1",
doi = "10.1038/cddis.2014.165",
language = "English",
volume = "5",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury

AU - Theus, M. H.

AU - Ricard, J.

AU - Glass, S. J.

AU - Travieso, L. G.

AU - Liebl, Daniel J

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Controlled cortical impact (CCI) injury

KW - Eph receptors

KW - Ephrins

KW - Traumatic brain injury (TBI)

UR - http://www.scopus.com/inward/record.url?scp=84901008799&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901008799&partnerID=8YFLogxK

U2 - 10.1038/cddis.2014.165

DO - 10.1038/cddis.2014.165

M3 - Article

C2 - 24810043

AN - SCOPUS:84901008799

VL - 5

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 5

M1 - e1207

ER -