RESUMO
Neuronal growth factors regulate the survival of neurons by their survival and death-promoting activity on distinct populations of neurons. The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) promote neuronal survival via tyrosine kinase (Trk) receptors, whereas NGF and BDNF can also induce apoptosis in developing neurons through p75(NTR) receptors in the absence of their respective Trk receptors. Using mutant mice and inactivation of neurotrophins and their receptors with antibodies in rats, we show that endogenous NT-3 induces death of adult BDNF-dependent, axotomized corticospinal neurons (CSNs). When NT-3 is neutralized, the neurons survive even without BDNF, suggesting complete antagonism. Whereas virtually all unlesioned and axotomized CSNs express both trkB and trkC mRNA, p75 is barely detectable in unlesioned CSNs but strongly upregulated in axotomized CSNs by day 3 after lesion, the time point when cell death occurs. Blocking either cortical TrkC or p75(NTR) receptors alone prevents death, indicating that the opposing actions of NT-3 and BDNF require their respective Trk receptors, but induction of death depends on p75(NTR) cosignaling. The results show that neuronal survival can be regulated antagonistically by neurotrophins and that neurotrophins can induce neuronal death in the adult mammalian CNS. We further present evidence that signaling of tyrosine kinase receptors of the trk family can be crucially involved in the promotion of neuronal death in vivo.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Neurônios/metabolismo , Neurotrofina 3/fisiologia , Tratos Piramidais/metabolismo , Animais , Anticorpos Bloqueadores/administração & dosagem , Axotomia , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Morte Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Antagonismo de Drogas , Feminino , Expressão Gênica/efeitos dos fármacos , Heterozigoto , Imuno-Histoquímica , Infusões Parenterais , Masculino , Camundongos , Camundongos Mutantes , Neurônios/efeitos dos fármacos , Neurotrofina 3/antagonistas & inibidores , Neurotrofina 3/farmacologia , Tratos Piramidais/anatomia & histologia , Tratos Piramidais/efeitos dos fármacos , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Receptor de Fator de Crescimento Neural , Receptor trkC/antagonistas & inibidores , Receptor trkC/genética , Receptor trkC/metabolismo , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
To study trophic dependencies of rat and mouse corticospinal neurons (CSN), we established a lesion model for the induction of death of analogous populations of CSN in these rodent species. Before lesion, CSN were retrogradely labeled with Fast Blue (FB). A stereotaxic cut lesion through the entire internal capsule (ICL) was used to axotomize CSN. The extent of axotomy was determined by application of a control tracer. In both species, FB-labeled CSN were localized in three major areas: (1) the sensory motor cortex; (2) the supplementary motor and medial prefrontal cortex; and (3) the somatosensory cortex. ICL does not lead to complete axotomy of CSN of the rat and mouse somatosensory cortex. In rats, ICL results in complete axotomy of CSN of the sensory motor cortex and incomplete axotomy of the caudal portion of the supplementary motor and medial prefrontal cortex. In mice, the area of axotomized CSN extends significantly further frontally. In both species, axotomy-induced death of CSN is observed in the center of the sensory motor cortex. This lesion model is useful for investigations on the response of CSN of the sensory motor cortex to lesion and therapeutic drugs.
