Notch/Neurogenin 3 Signalling is Involved in the Neuritogenic Actions of Oestradiol in Developing Hippocampal Neurones

Abstract

The ovarian hormone oestradiol promotes neuritic outgrowth in different neuronal types, by mechanisms that remain elusive. Recent studies have shown that the Notch-regulated transcription factor neurogenin 3 controls neuritogenesis. In the present study, we assessed whether oestradiol regulates neurogenin 3 in primary hippocampal neurones. As expected, neuritogenesis was increased in the cultures treated with oestradiol. However, the neuritogenic action of oestradiol was not prevented by ICI 182,780, an antagonist of classical oestrogen receptors (ERs). Oestradiol decreased the expression of Hairy and Enhancer of Split-1, a Notch-regulated gene that negatively controls the expression on neurogenin 3. Furthermore, oestradiol increased the expression of neurogenin 3 and regulated its distribution between the neuronal cell nucleus and the cytoplasm. The effect of oestradiol on neurogenin 3 expression was not blocked by antagonists of classical nuclear ER-mediated transcription and was not imitated by selective agonists of nuclear ERs. By contrast, G1, a ligand of G protein receptor 30/G protein-coupled ER, fully reproduced the effect of oestradiol on neuritogenesis, neurogenin 3 expression and neurogenin 3 subcellular localisation. Moreover, knockdown of neurogenin 3 in neurones by transfection with small interference RNA for neurogenin 3 completely abrogated the neuritogenic actions of oestradiol and G1. These results suggest that oestradiol regulates neurogenin 3 in primary hippocampal neurones by a nonclassical steroid signalling mechanism, which involves the down-regulation of Notch activity and the activation of G protein receptor 30/G protein-coupled ER or of other unknown G1 targets. In addition, our findings indicate that neurogenin 3 participates in the neuritogenic mechanisms of oestradiol in hippocampal neurones.

Neuroprotection in Parkinsonian-treated mice via estrogen receptor α activation requires G protein-coupled estrogen receptor 1

“…This study also reports that some transcripts were only inhibited by G15, indicating a specific GPER1 effect (Notas et al, 2012). In support, 17b-estradiol effects on neuritogenesis in hippocampal neurons were not mimicked by ERa or ERb agonists, and not blocked by ICI 182,780, but were rather produced by G1 and antagonized by G15 or by a small interfering RNA for GPER1 (Ruiz-Palmero et al, 2011. On the other hand, specific action of 17b-estradiol through ERa/b, but not via GPER1, is reported.…”

Molecular mechanisms involved in the regulation of neuritogenesis by estradiol: Recent advances

“…ER␣, via this signaling pathway [56] inhibits the activity of GSK3␤ in neural cells [56][57][58][59] and this may be involved in the neuritogenic action of the hormone, since GSK3␤ is crucial for neuronal polarization and axonal growth [60]. On the other hand, recent findings indicate that G1, an agonist of GPR30, which is known to regulate microtubule stability [61], imitates the effect of estradiol on developing hippocampal neurons, promoting dendritogenesis by the inhibition of Notch signaling [53]. This suggests that estradiol may in part regulate neuritogenesis acting on GPR30 or on other G1 targets (Fig.…”

“…Recent studies have shown that estradiol inhibits Notch signaling in developing hippocampal neurons [52,53], increasing the expression of Ngn3 and the growth of dendrites [53]. In addition, the downregulation of Ngn3 with specific siRNAs blocks the neuritogenic action of estradiol [53].…”

The neuroprotective actions of oestradiol and oestrogen receptors

“…Notch signalling is a conserved mechanism involved in direct cell-to-cell communication. In neurons, the inhibition of Notch signalling promotes neuronal differentiation 124 . Notch upregulates the expression of the…”