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J. Biol. Chem., Vol. 276, Issue 47, 44137-44145, November 23, 2001
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From the Departments of Infertility and spontaneous pregnancy
losses are an enduring problem to women's health. The establishment of
pregnancy depends on successful implantation, where a complex series of
interactions occurs between the heterogeneous cell types of the uterus
and blastocyst. Although a number of genes are implicated in
embryo-uterine interactions during implantation, genetic evidence
suggests that only a small number of them are critical to this process.
To obtain a global view and identify novel pathways of implantation, we used a dual screening strategy to analyze the expression of nearly 10,000 mouse genes by microarray analysis. Comparison of implantation and interimplantation sites by a conservative statistical approach revealed 36 up-regulated genes and 27 down-regulated genes at the
implantation site. We also compared the uterine gene expression profile
of progesterone-treated, delayed implanting mice to that of mice in
which delayed implantation was terminated by estrogen. The results show
up-regulation of 128 genes and down-regulation of 101 genes after
termination of the delayed implantation. A combined analysis of these
experiments showed specific up-regulation of 27 genes both at the
implantation site and during uterine activation, representing a broad
diversity of molecular functions. In contrast, the majority of genes
that were decreased in the combined analysis were related to host
immunity or the immune response, suggesting the importance of these
genes in regulating the uterine environment for the implanting
blastocyst. Collectively, we identified genes with recognized roles in
implantation, genes with potential roles in this process, and genes
whose functions have yet to be defined in this event. The
identification of unique genetic markers for the onset of implantation
signifies that genome-wide analysis coupled with functional assays is a
promising approach to resolve the molecular pathways required for
successful implantation.
Global Gene Expression Analysis to Identify Molecular Markers of
Uterine Receptivity and Embryo Implantation*,
§,§,, and
Pediatrics, ¶ Obstetrics
and Gynecology, and § Molecular and Integrative
Physiology, University of Kansas Medical Center, Kansas City,
Kansas 66160, the ** Department of Internal Medicine,
Diabetes and Endocrinology Research Center, University of Iowa,
Iowa City, Iowa 52242, and the Departments
of Medicine and Gastroenterology, Vanderbilt University Medical
Center, Nashville, Tennessee 37232
*
This work was supported in part by The Mellon Foundation; by
National Institutes of Health (NIH) Grants HD37677 (to J. R.), ES07814
(to S. K. Das), HD37394 (to B. C. P.), DK47297 (to R. N. D.),
HD12304, HD29968, HD33994 (to S. K. Dey); and by NICHD, NIH
Mental Retardation and Developmental Disabilities Center Grant HD02528.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The on-line version of this article (available at
http://www.jbc.org) contains Supplemental Tables IS and IIS.
A recipient of an NICHD (NIH) MERIT award. To whom
correspondence should be addressed: Dept. of Molecular and Integrative Physiology, University of Kansas Medical Center, MRRC 3017, 3901 Rainbow Blvd., Kansas City, KS 66160. Tel.: 913-588-6213; Fax: 913-588-5677; E-mail: sdey@kumc.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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