Interaction of estrogen receptors with insulin-like growth factor-I and Wnt signaling in the nervous system

Estradiol signaling through estrogen receptors in the nervous system involves a variety of rapid membrane/cytoplasm-initiated events that are integrated with different mechanisms of transcriptional regulation. Here we review the role of glycogen synthase kinase 3 (GSK3) and β-catenin in the coordination of membrane/cytoplasm-initiated and nuclear-initiated estrogen receptor signaling. Estradiol activates in vitro and in vivo the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in neural cells. By activating this pathway through estrogen receptors, estradiol increases the levels of inactive GSK3β (phosphorylated in serine 9). In turn, the inhibition of GSK3β increases the stability of β-catenin and its nuclear translocation. Then, β-catenin exerts two different transcriptional effects: (i) regulates β-catenin/T cell factor (TCF) mediated transcription in a similar but not identical way as Wnt ligands and (ii) regulates estrogen receptor mediated transcription after its association with estrogen receptor α. In addition, by the regulation of PI3K/Akt/GSK3/β-catenin pathway, other factors such as insulin-like growth factor-I (IGF-I) regulate estrogen receptor mediated transcription. Therefore, GSK3 and β-catenin allow the interaction of membrane/cytoplasm-initiated estrogen receptor signaling, IGF-I signaling, Wnt signaling and nuclear-initiated estrogen receptor signaling in the nervous system.