Estrogen deficiency leads to apoptosis in dopaminergic neurons in the medial preoptic area and arcuate nucleus of male mice

Mol Cell Neurosci. 2004 Dec;27(4):466-76. doi: 10.1016/j.mcn.2004.04.012.


The aromatase knockout (ArKO) mouse is unable to synthesize estrogens. Immunohistochemical studies on active caspase-3 and tyrosine hydroxylase (TH) revealed apoptosis of dopaminergic neurons in the medial preoptic area (MPO) and arcuate nucleus (Arc) of the hypothalamus of 1-year-old (1yo) male ArKO mice while no active caspase-3 was detected in wild type (WT). Furthermore, the number of TH-positive cells in the MPO and caudal Arc was significantly decreased in 1yo ArKO compared to WT. RNase protection assays support the presence of apoptosis in 1yo ArKO hypothalamus, revealing an up-regulation of pro-apoptotic genes: FASL, FADD, and caspase-8. Concomitantly, the ratio of bcl-2-related anti-apoptotic genes to pro-apoptotic genes in the hypothalamus of 1yo ArKO mice was significantly down-regulated. Previously, we have reported that no such changes were observed in the hypothalamus of female ArKO mice. Thus, we have provided direct evidence that estrogen is required to maintain the survival and functional integrity of dopaminergic neurons in the MPO and Arc of male, but not female mice.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Apoptosis / genetics*
  • Arcuate Nucleus of Hypothalamus / pathology
  • Arcuate Nucleus of Hypothalamus / physiopathology*
  • Aromatase / deficiency
  • Aromatase / genetics
  • Caspase 3
  • Caspase 8
  • Caspases / genetics
  • Caspases / metabolism
  • Cell Count
  • Cell Survival / genetics
  • Dopamine / metabolism*
  • Down-Regulation / genetics
  • Estrogens / biosynthesis
  • Estrogens / deficiency*
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Genes, bcl-2 / genetics
  • Male
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Knockout
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism*
  • Preoptic Area / pathology
  • Preoptic Area / physiopathology*
  • RNA, Messenger / metabolism
  • Tyrosine 3-Monooxygenase / metabolism
  • Up-Regulation / genetics


  • Adaptor Proteins, Signal Transducing
  • Estrogens
  • Fadd protein, mouse
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Fasl protein, mouse
  • Membrane Glycoproteins
  • RNA, Messenger
  • Aromatase
  • Tyrosine 3-Monooxygenase
  • Casp3 protein, mouse
  • Casp8 protein, mouse
  • Caspase 3
  • Caspase 8
  • Caspases
  • Dopamine