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Different Outcomes of Unliganded and Liganded Estrogen Receptor- on Neurite Outgrowth in PC12 Cells

Université de Rennes 1, Centre National de la Recherche Scientifique, Unité Mixte 6026, Equipe "Récepteur des œstrogènes et destinée cellulaire," 35042 Rennes, France

Address all correspondence and requests for reprints to: Gilles Flouriot, Equipe "Récepteur des œstrogènes et destinée cellulaire," Unité Mixte de Recherche Centre National de la Recherche Scientifique (UMR CNRS) 6026, Université de Rennes I, 35042 Rennes cedex, France. E-mail: gilles.flouriot{at}univ-rennes1.fr.

A precise description of the mechanisms by which estrogen receptor- (ER) exerts its influences on cellular growth and differentiation is still pending. Here, we report that the differentiation of PC12 cells is profoundly affected by ER. Importantly, depending upon its binding to 17β-estradiol (17βE2), ER is found to exert different effects on pathways involved in nerve growth factor (NGF) signaling. Indeed, upon its stable expression in PC12 cells, unliganded ER is able to partially inhibit the neurite outgrowth induced by NGF. This process involves a repression of MAPK and phosphatidylinositol 3-kinase/Akt signaling pathways, which leads to a negative regulation of markers of neuronal differentiation such as VGF and NFLc. This repressive action of unliganded ER is mediated by its D domain and does not involve its transactivation and DNA-binding domains, thereby suggesting that direct transcriptional activity of ER is not required. In contrast with this repressive action occurring in the absence of 17βE2, the expression of ER in PC12 cells allows 17βE2 to potentiate the NGF-induced neurite outgrowth. Importantly, 17βE2 has no impact on NGF-induced activity of MAPK and Akt signaling pathways. The mechanisms engaged by liganded ER are thus unlikely to rely on an antagonism of the inhibition mediated by the unliganded ER. Furthermore, 17βE2 enhances NGF-induced response of VGF and NFLc neuronal markers in PC12 clones expressing ER. This stimulatory effect of 17βE2 requires the transactivation functions of ER and its D domain, suggesting that an estrogen-responsive element-independent transcriptional mechanism is potentially relevant for the neuritogenic properties of 17βE2 in ER-expressing PC12 cells.