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The Postimplantation Embryo Differentially Regulates Endometrial Gene Expression and Decidualization

Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service (A.K., C.M.D., Y.K., Y.N., J.K.P.), and the Molecular Profiling Laboratory (T.S.), Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114; Cardiovascular Biology Research Program (C.T.E.), Howard Hughes Medical Institute, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104; and Animal Reproduction and Biotechnology Laboratory and the Department of Biomedical Sciences (T.R.H.), Colorado State University, Fort Collins, Colorado 80523

Address all correspondence and requests for reprints to: Dr. James K. Pru, Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, Harvard Medical School, Thier Research Building, Room 931, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: jpru{at}partners.org.

Transcriptomal changes in the uterine endometrium induced in response to the implanting embryo remain largely unknown. In this study, using Affymetrix mRNA expression microarray analysis, we identified genes differentially expressed in the murine endometrium in the presence or absence of the embryo. Compared with the pseudopregnant deciduoma induced by a mechanical stimulus in the absence of an embryo, approximately 1500 genes (753 up-regulated, 686 down-regulated; P < 0.05) were differentially expressed by at least 1.2-fold in the uterine decidua of pregnancy. Most of these genes fall into five major biological categories that include binding (45%), catalysis (24%), signal transduction (10%), transcriptional regulators (5%), and transporters (5%). This strong, embryo-induced transcriptomal impact represented approximately 10% of the total number of genes expressed in the decidualizing endometrium. Validation studies with mRNA and protein confirmed existence of the phylogenetically conserved, embryo-regulated genes involved in the following: 1) hemostasis and inflammation; 2) interferon signaling; 3) tissue growth and remodeling; and 4) natural killer cell function. Interestingly, whereas expression of many growth factors and their cognate receptors were not different between the decidual and deciduomal endometria, a number of proteases that degrade growth factors were selectively up-regulated in the decidual tissue. Increased expression of IGF and activin A neutralizing factors (i.e. HtrA1 and Fstl3) correlated with reduced stromal cell mitosis, tissue growth, and mitogenic signaling in the decidual endometrium. These results support the hypothesis that the implanting murine embryo takes a proactive role in modulating endometrial gene expression and development during early gestation.

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