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Researchers at
the University of Illinois at Urbana-Champaign report that
experiments involving mice -- to be detailed in the Proceedings of
the National Academy of Sciences -- indicate that the transcription
factor protein C/EBPb must be present in the uterus for pregnancy to
occur. The study appeared online in mid-January at
http://www.pnas.org/. Without
it, they say, an embryo cannot survive in uterine tissue or attach
to a mother's blood supply. Other genes also play roles, but C/EBPb
is critical for implantation of an embryo, said Milan K. Bagchi, a
professor of
molecular
and integrative physiology.
C/EBPb is scientifically known as CCAAT/enhancer binding protein
beta. It is regulated by the hormones estrogen and progesterone. In
normal conditions, the protein, driven mostly by progesterone, is
expressed rapidly and in large quantities during the critical
four-day implantation period in mice, Bagchi said.
During this period, an embryo attaches to the wall of the uterus,
advances into it, and eventually attaches to the blood supply and
forms the placenta. For a successful pregnancy to occur, stromal
cells of the uterus must be transformed into decidual cells, which
secrete nutrients that allow the embryo to survive until it plugs
into the blood supply. C/EBPb is necessary for decidualization, the
researchers discovered.
"This protein in the mouse is also in humans," Bagchi said. "We
believe it plays a critical role in human pregnancy. It is expressed
in the human endometrium at a time that coincides with the time of
implantation. We have demonstrated very clearly in the mouse that in
the absence of C/EBPb there is no decidualization. We transferred
viable mouse embryos from healthy mice into mice lacking the gene,
and pregnancy failed."
The project began more than four years ago.
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 First, researchers used DNA microarrays to identify gene
expression under normal and abnormal conditions during implantation.
After messenger RNA profiling zeroed in on C/EBPb's activity, the
researchers collaborated with Peter F. Johnson of the National
Cancer Institute's Laboratory of Protein Dynamics and Signaling, who
created mice that lacked the protein.
The experimental mice were then used to observe the relationships
of the hormones and their receptors with the protein under varying
conditions during the critical implantation period. In doing so,
researchers determined that C/EBPb is a critical mediator of steroid
hormone responsiveness in the uterus.
"This gene is expressed when the uterus is ready for embryo
attachment," said co-author Indrani C. Bagchi, a professor of
veterinary
biosciences in the U. of I.
College of Veterinary Medicine. "Its presence indicates a window
for success."
If the findings are replicated in human tissue, as expected, she
said, the protein's presence could become a vital gene marker for
predicting uterine readiness for pregnancy.
"The success rate for the practice of in vitro fertilization
currently is, on average, about 25 percent," she said. "The major
problem is that the conditions occurring when the embryo is
transferred often are not the best in the uterus. It's not known if
the uterus is ready to accept an embryo, so often multiple embryos
are transferred in hopes that one will attach. In future studies,
confirmation of C/EBPb as a marker that correctly indicates uterine
readiness for implantation in the human is likely to alleviate these
shortcomings."
Other co-authors of the paper were doctoral student Srinivasa
Raju Mantena, postdoctoral researchers Athilakshmi Kannan and Yong-Pil
Cheon, and research scientist Quanxi Li, all in Indrani Bagchi's
veterinary biosciences laboratory.
The National Institutes of Health funded the research.
[News release from
University of Illinois at Urbana-Champaign] |
