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, ERalpha has a neuroprotective effect, while ERbeta 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 FasL necessary to mediate estradiol-ERbeta apoptotic effect. These findings may explain the dichotomous effect of fetal estradiol on the adult neuronal number.
Nilsen
J
J
Department of Obstetrics and Gynecology, School of Medicine, Yale University, New Haven, Connecticut, USA.
Mor
G
G
Naftolin
F
F
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology*; D053222:Fas Ligand Protein; D005260:Female; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism*; D012727:Sex Characteristics; D019014:fas Receptor / Q000187:drug effects* / Q000378:metabolism*
D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D019014:fas Receptor; D004958:Estradiol