Estrogen-regulated developmental neuronal apoptosis is determined by estrogen receptor subtype and the Fas/Fas ligand system

Adult sexual dimorphism in neuronal cell number is controlled by estrogen exposure during a tightly defined period of rat brain development, The mechanisms of estrogen's effect are unknown; one possibility is regulation of programmed cell death (apoptosis), In this study we have shown that estradiol can function as a neuroprotective agent or an inducer of apoptosis, depending on the estrogen receptor-subtype present in the cell. Thus, ER alpha has a neuroprotective effect, while ER beta mediates the induction of apoptosis in neuronal cells. Moreover, we show that estrogen-induced apoptosis through ER-beta requires the expression of Fas- and Fas ligand (FasL) proteins, since the absence of FasL, in neurons prevents this effect, Furthermore, we demonstrate that microglia-secreted products induce the expression of Fast necessary to mediate estradiol-ER beta apoptotic effect. These findings may explain the dichotomous effect of fetal estradiol on the adult neuronal number. (C) 2000 John Wiley & Sons, Inc. J Neurobiol 43: 64-78, 2000.