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27
- 30 May 2005
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ANALYSIS
OF OESTROGEN RECEPTOR ALPHA FUNCTION IN THE
MOUSE BY GENE TARGETING
Tim M Wintermantel, Brenda
D Stride, Erich F Greiner and Günther
Schütz
Department of Molecular Biology of the Cell
I
German Cancer Research Center (DKFZ)
Im Neuenheimer Feld 280
D-69120 Heidelberg
Germany
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Oestrogens regulate several processes and organs
associated with female reproduction. It has previously
been shown that many actions of estrogens, including
the regulation of functions and organs essential
for female reproduction, are mediated by estrogen
receptor alpha (ERalpha).
ERalpha, a member of the nuclear receptor superfamily
of ligand-triggered transcription factors, regulates
gene expression in cells of estrogen-responsive
organs. Oestrogen receptor action, however, is tissue-specific
and involves different regulatory mechanisms. Using
cell type-specific and function-selective mouse
mutants, we set out to dissect these different mechanisms
in vivo. Whereas some oestrogen target genes are
activated via ER binding to estrogen response elements
(ERE) in the respective promotors, other target
genes can be regulated by protein interaction of
ER with different transcription factors. To separate
between these distinct regulatory mechanisms, a
germ line mutation was introduced into the mouse
gene for ERalpha which allowed to characterise and
distinguish functions dependent on ER-binding to
EREs on DNA from those mediated by protein/protein
interaction.
An alternative mechanism of gene regulation by ERalpha
is the oestradiol-independent activation by phosphorylation,
which can occur following stimulation by growth
factors. A mouse mutant was generated harboring
a point mutation in the ERalpha gene that no longer
allows phosphorylation of ERalpha on Serine 122,
and this model was used to study ligand-independent
ERalpha actions in vivo. The effects of both function-selective
ERalpha mutations on the female reproductive tract
will be presented.
Cell type/tissue-specific mutations of the estrogen
receptor have been generated using the Cre-loxP
system in order to evaluate tissue-specific functions
of oestrogen. The gene for ERalpha was selectively
inactivated in parenchymal cells of the liver, in
mammary epithelial cells and brain, respectively.
Inactivation of ERalpha in brain severely affects
hypothalamic estrogen feedback, leading to major
disturbances of the female reproductive tract at
the onset of puberty. The phenotypes of tissue-specific
estrogen receptor alpha mutants will be discussed.
List
of abstracts from the 3rd International Conference
on the Female Reproductive Tract
