EphB3 limits the expansion of neural progenitor cells in the subventricular zone by regulating p53 during homeostasis and following traumatic brain injury.
Ephrins and Eph receptor(s) have recently been implicated in regulating neurogenesis in the adult subventricular zone (SVZ) and rostral migratory stream. Here, we examined the role of ephrinB3-EphB3 signaling in mediating the SVZ response to traumatic brain injury (TBI). Analysis of EphB3 expression showed colocalization with glial fibrillary acidic protein-positive neural stem progenitor cells (NSPCs) and doublecortin-positive neuroblasts, whereas ephrinB3 was expressed outside the neurogenic region. TBI resulted in a significant reduction in EphB3 expression, which coincided with enhanced NSPC survival and proliferation at 3 and 7 days postinjury. Analysis of mice lacking either ephrinB3 (ephrinB3(-/-)) or EphB3 (EphB3(-/-)) showed a significant increase in bromodeoxyuridine (BrdU) incorporation and Ki67 immunoreactivity in the SVZ. Interestingly, cell death was dissimilar between knockout mice, where cell death was reduced in EphB3(-/-) but increased in ephrinB3(-/-) mice. Lateral ventricle infusion of soluble preclustered ephrinB3-Fc reversed the proliferative and cell death defects in ephrinB3(-/-) but not EphB3(-/-) mice and prevented TBI-induced proliferation in wild-type NSPCs. Coincidently, tumor suppressor p53 expression was increased following EphB3 stimulation and is reduced in the absence of either EphB3 or ephrinB3. Furthermore, pharmacological inhibition and siRNA knockdown of p53-attenuated ephrinB3-Fc-mediated growth suppression while having no effect on cell death in cultured NSPCs. These data demonstrate that EphB3 signaling suppresses NSPC proliferation in a p53-dependent manner, induces cell death in the absence of ligand stimulation and is transiently reduced in the SVZ to initiate the expansion and survival of endogenous adult NSPCs following TBI.
Theus
Michelle H
MH
The Miami Project to Cure Paralysis and Department of Neurological Surgery, University of Miami, Miami, Florida 33136, USA.
Ricard
Jerome
J
Bethea
John R
JR
Liebl
Daniel J
DJ
D000375:Aging; D000818:Animals; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology / Q000378:metabolism*; D036389:Ephrin-B3 / Q000172:deficiency / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D036223:Receptor, EphB3 / Q000172:deficiency / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D036389:Ephrin-B3; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D036223:Receptor, EphB3