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

J Neurobiol. 2000 Apr;43(1):64-78. doi: 10.1002/(sici)1097-4695(200004)43:1<64::aid-neu6>;2-7.


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.

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects*
  • Apoptosis / physiology*
  • Brain / cytology
  • Brain / drug effects
  • Brain / embryology
  • Cell Culture Techniques
  • Cell Division / drug effects
  • Cell Division / physiology
  • Estradiol / metabolism*
  • Estradiol / pharmacology*
  • Fas Ligand Protein
  • Female
  • Membrane Glycoproteins / drug effects*
  • Membrane Glycoproteins / metabolism*
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism*
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / genetics*
  • Receptors, Estrogen / metabolism*
  • Sex Characteristics
  • fas Receptor / drug effects*
  • fas Receptor / metabolism*


  • Fas Ligand Protein
  • Faslg protein, rat
  • Membrane Glycoproteins
  • Neuroprotective Agents
  • RNA, Messenger
  • Receptors, Estrogen
  • fas Receptor
  • Estradiol