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

A precise description of the mechanisms by which estrogen receptor-alpha (ER alpha) 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 alpha. Importantly, depending upon its binding to 17 beta-estradiol (17 beta E2), ER alpha 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 alpha 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 alpha is mediated by its D domain and does not involve its transactivation and DNA-binding domains, thereby suggesting that direct transcriptional activity of ER alpha is not required. In contrast with this repressive action occurring in the absence of 17 beta E2, the expression of ER alpha in PC12 cells allows 17 beta E2 to potentiate the NGF-induced neurite outgrowth. Importantly, 17 beta E2 has no impact on NGF-induced activity of MAPK and Akt signaling pathways. The mechanisms engaged by liganded ER alpha are thus unlikely to rely on an antagonism of the inhibition mediated by the unliganded ER alpha. Furthermore, 17 beta E2 enhances NGF-induced response of VGF and NFLc neuronal markers in PC12 clones expressing ER alpha. This stimulatory effect of 17 beta E2 requires the transactivation functions of ER alpha and its D domain, suggesting that an estrogen-responsive element-independent transcriptional mechanism is potentially relevant for the neuritogenic properties of 17 beta E2 in ER alpha-expressing PC12 cells. (Endocrinology 150: 200-211, 2009)