Uterine Foxl2 regulates the adherence of the Trophectoderm cells to the endometrial epithelium
Tóm tắt
Forkhead Transcription Factor L2 (FOXL2) is a member of the forkhead family with important roles in reproduction. Recent studies showed that FOXL2 is expressed in human and bovine endometrium and that its levels fluctuate during pregnancy. In this study, we aimed at evaluating the expression and function of FOXL2 in embryo implantation. Mouse uteri at different days of pregnancy were isolated and analyzed for the expression and localization of FOXL2. A lentiviral strategy was further employed to either knockdown or overexpress FOXL2 in non-receptive human endometrial AN3-CA cells and in receptive Ishikawa cells, respectively. These genetically modified cells were compared to cells infected with a control lentivirus to determine the function of FOXL2 in trophectoderm cells adherence to Endometrial Epithelium was associated with the expression of genes known to be involved in acquisition of uterine receptivity. We report that FOXL2 is expressed in both, the luminal epithelium and the myometrium of the mouse uterus and that its expression declines prior to implantation. We found that endometrial cells expressing low FOXL2 levels, either endogenous or genetically manipulated, were associated with a higher attachment rate of mouse blastocysts or human Jeg3 spheroids and mouse blastocysts. In accordance, low-FOXL2 levels were associated with changes in the expression level of components of the Wnt/Fzd and apoptotic pathways, both of which are involved in uterine receptivity. Furthermore, FOXL2 expression was inversely correlated with G-protein signaling protein 2 (Rgs2) and cytokine expression. These results suggest that FOXL2 interferes with embryo attachment. Better understanding of the function of FOXL2 in the uterus would possibly suggest novel strategies for treatment of infertility attributed to repeated implantation failure.
Tài liệu tham khảo
Carlsson P, Mahlapuu M. Forkhead transcription factors: key players in development and metabolism. Dev Biol. 2002;250:1–23.
Zlotogora J, Sagi M, Cohen T. The blepharophimosis, ptosis, and epicanthus inversus syndrome: delineation of two types. Am J Hum Genet. 1983;35:1020–7.
Batista F, Vaiman D, Dausset J, Fellous M, Veitia RA. Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics. Proc Natl Acad Sci U S A. 2007;104:3330–5.
Georges A, L’Hote D, Todeschini AL, Auguste A, Legois B, Zider A, Veitia RA. The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells. elife. 2014;3
Caburet S, Georges A, L'Hote D, Todeschini AL, Benayoun BA, Veitia RA. The transcription factor FOXL2: at the crossroads of ovarian physiology and pathology. Mol Cell Endocrinol. 2012;356:55–64.
Elzaiat M, Jouneau L, Thepot D, Klopp C, Allais-Bonnet A, Cabau C, Andre M, Chaffaux S, Cribiu EP, Pailhoux E, Pannetier M. High-throughput sequencing analyses of XX genital ridges lacking FOXL2 reveal DMRT1 up-regulation before SOX9 expression during the sex-reversal process in goats. Biol Reprod. 2014;91:153.
Huang ZP, Ni H, Yang ZM, Wang J, Tso JK, Shen QX. Expression of regulator of G-protein signalling protein 2 (RGS2) in the mouse uterus at implantation sites. Reproduction. 2003;126:309–16.
Ladds G, Zervou S, Vatish M, Thornton S, Davey J. Regulators of G protein signalling proteins in the human myometrium. Eur J Pharmacol. 2009;610:23–8.
Blount AL, Schmidt K, Justice NJ, Vale WW, Fischer WH, Bilezikjian LM. FoxL2 and Smad3 coordinately regulate follistatin gene transcription. J Biol Chem. 2009;284:7631–45.
McTavish KJ, Nonis D, Hoang YD, Shimasaki S. Granulosa cell tumor mutant FOXL2C134W suppresses GDF-9 and activin A-induced follistatin transcription in primary granulosa cells. Mol Cell Endocrinol. 2013;372:57–64.
Sugawara K, Kizaki K, Herath CB, Hasegawa Y, Hashizume K. Transforming growth factor beta family expression at the bovine feto-maternal interface. Reprod Biol Endocrinol. 2010;8:120.
Governini L, Carrarelli P, Rocha AL, Leo VD, Luddi A, Arcuri F, Piomboni P, Chapron C, Bilezikjian LM, Petraglia F. FOXL2 in human endometrium: hyperexpressed in endometriosis. Reprod Sci. 2014;21:1249–55.
Hu S, Yao G, Wang Y, Xu H, Ji X, He Y, Zhu Q, Chen Z, Sun Y. Transcriptomic changes during the pre-receptive to receptive transition in human endometrium detected by RNA-Seq. J Clin Endocrinol Metab. 2014;99(12):E2744–53.
Popovici RM, Betzler NK, Krause MS, Luo M, Jauckus J, Germeyer A, Bloethner S, Schlotterer A, Kumar R, Strowitzki T, von Wolff M. Gene expression profiling of human endometrial-trophoblast interaction in a coculture model. Endocrinology. 2006;147:5662–75.
Bellessort B, Bachelot A, Heude E, Alfama G, Fontaine A, Le Cardinal M, Treier M, Levi G. Role of Foxl2 in uterine maturation and function. Hum Mol Genet. 2015;
Blount AL, Vaughan JM, Vale WW, Bilezikjian LM. A Smad-binding element in intron 1 participates in activin-dependent regulation of the follistatin gene. J Biol Chem. 2008;283:7016–26.
Aboussahoud W, Bruce C, Elliott S, Fazeli A. Activation of toll-like receptor 5 decreases the attachment of human trophoblast cells to endometrial cells in vitro. Hum Reprod. 2010;25:2217–28.
Kang YJ, Forbes K, Carver J, Aplin JD. The role of the osteopontin-integrin alphavbeta3 interaction at implantation: functional analysis using three different in vitro models. Hum Reprod. 2014;29:739–49.
Eozenou C, Mansouri-Attia N, Aubert J, Reinaud P, Giraud-Delville C, Taghouti G, Galio L, Everts RE, Degrelle S, Richard C, et al. Gene expression profiles of bovine caruncular and intercaruncular endometrium at implantation. Physiol Genomics. 2009;39:14–27.
Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier AC, Treier M. The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development. 2004;131:933–42.
Liu Y, Kodithuwakku SP, Ng PY, Chai J, Ng EH, Yeung WS, Ho PC, Lee KF. Excessive ovarian stimulation up-regulates the Wnt-signaling molecule DKK1 in human endometrium and may affect implantation: an in vitro co-culture study. Hum Reprod. 2010;25:479–90.
Rahnama F, Thompson B, Steiner M, Shafiei F, Lobie PE, Mitchell MD. Epigenetic regulation of E-cadherin controls endometrial receptivity. Endocrinology. 2009;150:1466–72.
Sonderegger S, Pollheimer J, Knofler M. Wnt signalling in implantation, decidualisation and placental differentiation--review. Placenta. 2010;31:839–47.
Hayashi K, Erikson DW, Tilford SA, Bany BM, Maclean JA 2nd, Rucker EB 3rd, Johnson GA, Spencer TE. Wnt genes in the mouse uterus: potential regulation of implantation. Biol Reprod. 2009;80:989–1000.
Moumne L, Batista F, Benayoun BA, Nallathambi J, Fellous M, Sundaresan P, Veitia RA. The mutations and potential targets of the forkhead transcription factor FOXL2. Mol Cell Endocrinol. 2008;282:2–11.
Hess AP, Hamilton AE, Talbi S, Dosiou C, Nyegaard M, Nayak N, Genbecev-Krtolica O, Mavrogianis P, Ferrer K, Kruessel J, et al. Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators. Biol Reprod. 2007;76:102–17.
Eozenou C, Vitorino Carvalho A, Forde N, Giraud-Delville C, Gall L, Lonergan P, Auguste A, Charpigny G, Richard C, Pannetier M, Sandra O. FOXL2 is regulated during the bovine estrous cycle and its expression in the endometrium is independent of conceptus-derived interferon tau. Biol Reprod. 2012;87:32.
Boulanger L, Pannetier M, Gall L, Allais-Bonnet A, Elzaiat M, Le Bourhis D, Daniel N, Richard C, Cotinot C, Ghyselinck NB, Pailhoux E. FOXL2 is a female sex-determining gene in the goat. Curr Biol. 2014;24:404–8.
Pailhoux E, Vigier B, Chaffaux S, Servel N, Taourit S, Furet JP, Fellous M, Grosclaude F, Cribiu EP, Cotinot C, Vaiman D. A 11.7-kb deletion triggers intersexuality and polledness in goats. Nat Genet. 2001;29:453–8.
Pailhoux E, Vigier B, Vaiman D, Servel N, Chaffaux S, Cribiu EP, Cotinot C. Ontogenesis of female-to-male sex-reversal in XX polled goats. Dev Dyn. 2002;224:39–50.
Uda M, Ottolenghi C, Crisponi L, Garcia JE, Deiana M, Kimber W, Forabosco A, Cao A, Schlessinger D, Pilia G. Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development. Hum Mol Genet. 2004;13:1171–81.
Richards JS, Pangas SA. The ovary: basic biology and clinical implications. J Clin Invest. 2010;120:963–72.
Mohamed OA, Jonnaert M, Labelle-Dumais C, Kuroda K, Clarke HJ, Dufort D. Uterine Wnt/beta-catenin signaling is required for implantation. Proc Natl Acad Sci U S A. 2005;102:8579–84.
Hayashi K, Burghardt RC, Bazer FW, Spencer TE. WNTs in the ovine uterus: potential regulation of periimplantation ovine conceptus development. Endocrinology. 2007;148:3496–506.
Hayashi K, Yoshioka S, Reardon SN, Rucker EB, 3rd, Spencer TE, DeMayo FJ, Lydon JP, MacLean JA, 2nd: WNTs in the neonatal mouse uterus: potential regulation of endometrial gland development. Biol Reprod 2011, 84:308–319.
Di Pietro C, Cicinelli E, Guglielmino MR, Ragusa M, Farina M, Palumbo MA, Cianci A. Altered transcriptional regulation of cytokines, growth factors, and apoptotic proteins in the endometrium of infertile women with chronic endometritis. Am J Reprod Immunol. 2013;69:509–17.
Abot A, Fontaine C, Raymond-Letron I, Flouriot G, Adlanmerini M, Buscato M, Otto C, Berges H, Laurell H, Gourdy P, et al. The AF-1 activation function of estrogen receptor alpha is necessary and sufficient for uterine epithelial cell proliferation in vivo. Endocrinology. 2013;154:2222–33.
Oliveira-Dos-Santos AJ, Matsumoto G, Snow BE, Bai D, Houston FP, Whishaw IQ, Mariathasan S, Sasaki T, Wakeham A, Ohashi PS, et al. Regulation of T cell activation, anxiety, and male aggression by RGS2. Proc Natl Acad Sci U S A. 2000;97:12272–7.
Nie GY, Li Y, Hampton AL, Salamonsen LA, Clements JA, Findlay JK. Identification of monoclonal nonspecific suppressor factor beta (mNSFbeta) as one of the genes differentially expressed at implantation sites compared to interimplantation sites in the mouse uterus. Mol Reprod Dev. 2000;55:351–63.