RESUMO
Nerve growth factor (NGF) induces dramatic axon growth from responsive embryonic peripheral neurons. However, the roles of the various NGF-triggered signaling cascades in determining specific axon morphological features remain unknown. Here, we transfected activated and inhibitory mutants of Trk effectors into sensory neurons lacking the proapoptotic protein Bax. This allowed axon growth to be studied in the absence of NGF, enabling us to observe the contributions of individual signaling mediators. While Ras was both necessary and sufficient for NGF-stimulated axon growth, the Ras effectors Raf and Akt induced distinct morphologies. Activated Raf-1 caused axon lengthening comparable to NGF, while active Akt increased axon caliber and branching. Our results suggest that the different Trk effector pathways mediate distinct morphological aspects of developing neurons.
Assuntos
Gânglios Espinais/embriologia , Gânglios Espinais/metabolismo , Cones de Crescimento/metabolismo , Neurônios Aferentes/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas c-raf/deficiência , Proteínas Proto-Oncogênicas/deficiência , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Diferenciação Celular/genética , Tamanho Celular/genética , Feminino , Feto , Gânglios Espinais/citologia , Expressão Gênica/fisiologia , Cones de Crescimento/ultraestrutura , MAP Quinase Quinase 1 , Masculino , Camundongos , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator de Crescimento Neural/metabolismo , Neurônios Aferentes/citologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-raf/genética , Receptores Proteína Tirosina Quinases/genética , Receptor trkA/genética , Receptor trkA/metabolismo , Receptor trkC/genética , Receptor trkC/metabolismo , Transdução de Sinais/genética , Proteína X Associada a bcl-2 , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
Robust axon regeneration occurs after peripheral nerve injury through coordinated activation of a genetic program and local intracellular signaling cascades. Although regeneration-associated genes are being identified with increasing frequency, most aspects of regeneration-associated intracellular signaling remain poorly understood. Two independent studies now report that upregulation of cAMP is a component of the PNS regeneration program that can be exploited to enhance axon regeneration through the normally inhibitory CNS environment.
Assuntos
Cones de Crescimento/metabolismo , Regeneração Nervosa/fisiologia , Traumatismos dos Nervos Periféricos , Transdução de Sinais/fisiologia , Animais , AMP Cíclico/metabolismo , Citocinas/metabolismo , Gânglios Espinais/citologia , Gânglios Espinais/lesões , Gânglios Espinais/metabolismo , Cones de Crescimento/ultraestrutura , Substâncias de Crescimento/metabolismo , Humanos , Nervos Periféricos/metabolismo , Nervos Periféricos/fisiopatologiaRESUMO
Neuronal morphological differentiation is regulated by numerous polypeptide growth factors (neurotrophic factors). Recently, significant progress has been achieved in clarifying the roles of neurotrophins as well as glial cell line-derived neurotrophic factor family members in peripheral axon elongation during development. Additionally, advances have been made in defining the signal transduction mechanisms employed by these factors in mediating axon morphological responses. Several studies addressed the role of neurotrophic factors in regenerative axon growth and suggest that signaling mechanisms in addition to those triggered by receptor tyrosine kinases may be required for successful peripheral nervous system regeneration. Finally, recent investigations demonstrate that neurotrophic factors can enhance axon growth after spinal cord injuries.