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A Combined Approach for Gene Discovery Identifies Insulin-Like Growth Factor-Binding Protein-Related Protein 1 as a New Gene Implicated in Human Endometrial Receptivity

Instituto Valenciano de Infertilidad (IVI-FIVIER) (F.D., A.C., J.M., A.P., C.S.) and Department of Pediatrics, Obstetrics, and Gynecology (F.D., J.M., A.P., C.S.), School of Medicine, University of Valencia, 46010 Valencia; and Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) (S.A., J.L.C.), Universidad Autónoma of Madrid, Cantoblanco, 28049 Madrid, Spain

Address all correspondence and requests for reprints to: Carlos Simón, M.D., Instituto Valenciano de Infertilidad (IVI-FIVIER), C/Policia Local, 3, 46015 Valencia, Spain. E-mail: csimon{at}interbook.net.

In the past, human endometrial receptivity has been investigated by chasing specific molecules throughout the menstrual cycle. Now the genomic approach allows us to investigate the hierarchical contribution of a high number of genes to a specific function. In this study, we analyzed differentially the gene expression pattern of 375 human cytokines, chemokines, and related factors, plus that of their receptors, in endometrial receptivity. To do this, we used a combined approach of human endometrium and cell lines. We have compared the gene expression pattern in receptive vs. prereceptive human endometria and contrasted the results with gene expression in the highly adhesive cell line (to JAR cells and mouse blastocysts) RL95-2 vs. HEC-1A, a cell line with markedly less adhesiveness. IGF-binding protein-related protein 1 (IGFBP-rP1), also known as IGFBP-7/mac 25, was the second most up-regulated gene in both of the investigated models. These results were corroborated by performing RT-PCR on the same RNA samples and validated by quantitative fluorescent RT-PCR and in situ hybridization in endometrium throughout the menstrual cycle. Interestingly, a 35-fold increase in expression during the receptive phase was compared with the prereceptive phase followed by a sharp increase in the late luteal. Further quantitative fluorescent RT-PCR experiments using the epithelial and stromal endometrial fraction throughout the menstrual cycle confirmed that IGFBP-rP1 expression was localized in the epithelial and stromal compartments and up-regulated mainly in the latter. In situ experiments confirmed the endometrial localization and regulation of IGFBP-rP1 mRNA. At the protein level, IGFBP-rP1 was localized by immunohistochemistry at the apical part of the luminal and glandular epithelium, stromal, and endothelial cells. In conclusion, using a genomic approach with a combined experimental design of receptivity in vivo and in vitro, we have discovered the implication of IGFBP-rP1 in endometrial physiology, which seems related to endometrial receptivity.

This work was supported by Grants SAF2001-2948, MT1999-B24364784 MCYT and 1FD97-0582 from the Spanish Government and an institutional grant from the Fundación Ramon Areces.

F.D. and S.A. made equal contributions to this work.

Abbreviations: E₂, 17ß-Estradiol; EEC, endometrial epithelial cell; IGFBP, IGF-binding protein; IGFBP-rP1, IGF-binding protein-related protein 1; LH+2, prereceptive phase; LH+7, receptive phase; P, progesterone; QF-PCR, quantitative fluorescent RT-PCR; SSC, saline sodium citrate; TIMP, tissue inhibitor of metalloproteinase.

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