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Identification, Characterization, and Regulation of the Canonical Wnt Signaling Pathway in Human Endometrium

Department of Gynecology and Obstetrics (S.T., N.R.N., L.C.K., J.H., S.L., A.G., L.C.G.), Stanford University, Stanford, California 94305-5317; Stratagene (M.v.W.), La Jolla, California 92037; Department of Obstetrics & Gynecology (B.A.L.), University of North Carolina, Chapel Hill, North Carolina 27599; Department of Obstetrics, Gynecology, and Reproductive Sciences (R.N.T.), University of California, San Francisco, California 94143; and Department of Obstetrics and Gynecology (E.S.), Zagreb University School of Medicine, 10000 Zagreb, Croatia

Address all correspondence and requests for reprints to: Linda C. Giudice, M.D., Ph.D., Center for Research on Women’s Health and Reproductive Medicine, Division of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Stanford University, Stanford, California 94305-5317. E-mail: giudice{at}stanford.edu.

Members of the Wnt family of signaling molecules are important in cell specification and epithelial-mesenchymal interactions, and targeted gene deletion of Wnt-7a in mice results in complete absence of uterine glands and infertility. To assess potential roles of the Wnt family in human endometrium, an endocrine-responsive tissue, we investigated in the proliferative and secretory phases of the menstrual cycle, endometrial expression of several Wnt ligands (Wnt-2, Wnt-3, Wnt-4, Wnt-5a, Wnt-7a, and Wnt-8b), receptors [Frizzled (Fz)-6 and low-density lipoprotein receptor-related protein (LRP)-6], inhibitors [FrpHE and Dickkopf (Dkk)-1], and downstream effectors (Dishevelled-1, glycogen synthase kinase-3ß, and ß-catenin) by RT-PCR, real-time PCR and in situ hybridization. No significant menstrual cycle dependence of the Wnt ligands (except Wnt-3), receptors, or downstream effectors, was observed. Wnt-3 increased 4.7-fold in proliferative compared with secretory endometrium (P < 0.05). However, both inhibitors showed dramatic changes during the cycle, with 22.2-fold down-regulation (P < 0.05) of FrpHE and 234.3-fold up-regulation (P < 0.001) of Dkk-1 in the secretory, compared with the proliferative phase. In situ hybridization revealed cell-specific expression of different Wnt family genes in human endometrium. Wnt-7a was exclusively expressed in the luminal epithelium, and Fz-6 and ß-catenin were expressed in both epithelium and stroma, without any apparent change during the cycle. Both FrpHE and Dkk-1 expression were restricted to the stroma, during the proliferative and secretory phase, respectively. These unique expression patterns of Wnt family genes in different cell types of endometrium and the differential regulation of the inhibitors during the proliferative and secretory phase of the menstrual cycle strongly suggest functions for a Wnt signaling dialog between epithelial and stromal components in human endometrium. Also, they underscore the likely importance of this family during endometrial development, differentiation and implantation.

This work is supported by the National Institutes of Health (NIH) Specialized Cooperative Centers Program in Reproductive Research (National Institute of Child Health and Human Development HD 31398) and the NIH Office of Women’s Health Research (to L.C.G., B.A.L., R.N.T.), the NIH Women’s Reproductive Health Research Career Development Program (to L.C.K.), and the German Research Foundation [Deutsche Forschungsgemeinschaft GE 1173/1-1 (to A.G.)] and the Scientific Research Fund of the Croatian Ministry of Science (Grant No. 108-250).

Abbreviations: Ct, Threshold cycle; Dkk, Dickkopf; Dvl, Dishevelled; Fz, frizzled; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GOI, gene of interest; GSK, glycogen synthase kinase; LRP, low-density lipoprotein receptor-related protein; RT, reverse transcription.

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