Pj. Shughrue et al., RESPONSES IN THE BRAIN OF ESTROGEN-RECEPTOR ALPHA-DISRUPTED MICE, Proceedings of the National Academy of Sciences of the United Statesof America, 94(20), 1997, pp. 11008-11012
These studies sought to determine if neurons in the estrogen receptor-
ct knockout (ER alpha KO) mouse brain concentrated 16 alpha-[I-125]iod
o-11 beta-methoxy-17 beta-estradiol (I-125-estrogen), and if so, wheth
er estrogen binding augmented the expression of progesterone receptor
(PR) mRNA. Mice were injected with I-125-estrogen and cryostat section
s thaw mounted onto emulsion-coated glides. After 30-90 days of exposu
re, cells with a nuclear uptake and retention of I-125-estrogen were o
bserved in a number of ER alpha KO mouse brain regions including the p
reoptic nucleus and arcuate nucleus of the hypothalamus, bed nucleus o
f the stria terminalis, and amygdala, although the number of labeled c
ells and intensity of nuclear concentration was markedly attenuated wh
en compared with wild-type littermates. Competition studies with exces
s 17 beta-estradiol, diethylstilbestrol, or moxestrol, But not with R5
020 or dihydrotestosterone, prevented the nuclear concentration of I-1
25-estrogen. To determine if the low level of estrogen binding was cap
able of regulating gene expression, in situ hybridization was used to
evaluate PR mRNA in the brain, ER alpha KO and wild-type mice were ova
riectomized and treated with vehicle or 17 beta-estradiol, and brains
were sectioned and hybridized with a PR cRNA probe, Analysis of hybrid
ization signal revealed a similar, low level of PR mRNA in ovariectomi
zed wild-type and homozygous mice, and a marked increase in expression
after treatment of ovariectomized animals with 17 beta-estradiol, wit
h the level of hybridization signal being significantly higher in wild
-type animals when compared with ER alpha KO mice, The results demonst
rate that estrogen binds in the ER alpha KO brain and is capable of mo
dulating PR gene expression, thus supporting the presence and function
ality of a nonclassical estrogen receptor.