RESUMO
The oestradiol plays an important role in normal brain development and exerts neuroprotective actions. Oestradiol is mainly produced in the ovary and in addition is locally synthesised in the brain. Most of the oestradiol functions have been associated with its capacity to directly bind and dimerize "classical oestrogen receptors" (ERs), alpha and beta. The ERs' actions have been classified as "genomic" and "non-genomic" depending on whether protein synthesis occurs through ER driven transcription or not. Indeed, recent evidence suggests that oestrogen may also act as a more general "trophic factor". Hence, we have studied the capacity of oestradiol to activate the PI3K/Akt pathway and its implication in axonal growth and neuronal morphogenesis. Our data show that when oestrogen receptors are blocked the axonal and dendritic lengths are reduced in mouse primary neurons. We found that Akt/Rheb/mTORC1 responds to ER activation in neurons and that some elements of this pathway are able to restore a normal neuronal morphology even in the presence of oestrogen receptor antagonist. All these data demonstrate a new mechanism regulated by oestradiol, at least in neuronal morphogenesis.
Assuntos
Estradiol , Complexos Multiproteicos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Linhagem Celular , Estradiol/administração & dosagem , Estradiol/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/metabolismo , Feminino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Neuroblastoma/metabolismo , Neurônios/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Transdução de SinaisRESUMO
Oestradiol acts in the brain by multiple mechanisms, including the regulation of transcriptional activity through classical oestrogen receptors, α and ß, and by the activation of membrane/cytoplasm-initiated signalling cascades. In neuroblastoma cells, primary neurones in culture and in the brain in vivo, oestradiol activates the phosphoinositide 3-kinase/Akt/glycogen synthase kinase 3 signalling pathway by a mechanism involving oestrogen receptor α. Through this pathway, oestradiol regulates the stability of ß-catenin, induces the translocation of ß-catenin to the cell nucleus and regulates ß-catenin-mediated transcription through the T cell factor/DNA complex. Genomic analyses in neuroblastoma cells have revealed that the set of genes regulated by oestradiol through ß-catenin is not identical to that regulated by the Wnt signalling pathway, revealing a new mechanism for oestradiol signalling in neurones.