RESUMEN
We demonstrate that EphB3 receptors mediate oligodendrocyte (OL) cell death in the injured spinal cord through dependence receptor mechanism. OLs in the adult spinal cord express EphB3 as well as other members of the Eph receptor family. Spinal cord injury (SCI) is associated with tissue damage, cellular loss and disturbances in EphB3-ephrinB3 protein balance acutely (days) after the initial impact creating an environment for a dependence receptor-mediated cell death to occur. Genetic ablation of EphB3 promotes OL survival associated with increased expression of myelin basic protein and improved locomotor function in mice after SCI. Moreover, administration of its ephrinB3 ligand to the spinal cord after injury also promotes OL survival. Our in vivo findings are supported by in vitro studies showing that ephrinB3 administration promotes the survival of both oligodendroglial progenitor cells and mature OLs cultured under pro-apoptotic conditions. In conclusion, the present study demonstrates a novel dependence receptor role of EphB3 in OL cell death after SCI, and supports further development of ephrinB3-based therapies to promote recovery.
Asunto(s)
Apoptosis , Oligodendroglía/fisiología , Receptor EphB3/fisiología , Traumatismos de la Médula Espinal/metabolismo , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Efrina-B3/farmacología , Efrina-B3/uso terapéutico , Femenino , Ratones Noqueados , Recuperación de la Función , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patologíaRESUMEN
Brain-derived neurotrophic factor (BDNF) was studied initially for its role in sensory neuron development. Ablation of this gene in mice leads to death shortly after birth, and abnormalities have been found in both the peripheral and central nervous systems. BDNF and its tyrosine kinase receptor, TrkB, are expressed in hypothalamic nuclei associated with satiety and locomotor activity. In heterozygous mice, BDNF gene expression is reduced and we find that all heterozygous mice exhibit abnormalities in eating behavior or locomotor activity. We also observe this phenotype in independently derived inbred and hybrid BDNF mutant strains. Infusion with BDNF or NT4/5 can transiently reverse the eating behavior and obesity. Thus, we identify a novel non-neurotrophic function for neurotrophins and indicate a role in behavior that is remarkably sensitive to alterations in BDNF activity.