Homeobox Genes Critically Regulate Embryo Implantation by Controlling Paracrine Signaling between Uterine Stroma and Epithelium
The mammalian Msx homeobox genes, Msx1 and Msx2, encode transcription factors that control organogenesis and tissue interactions during embryonic development. We observed overlapping expression of these factors in uterine epithelial and stromal compartments of pregnant mice prior to embryo implantation. Conditional ablation of both Msx1 and Msx2 in the uterus resulted in female infertility due to a failure in implantation. In these mutant mice (Msx1/2d/d), the uterine epithelium exhibited persistent proliferative activity and failed to attach to the embryos. Gene expression profiling of uterine epithelium and stroma of Msx1/2d/d mice revealed an elevated expression of several members of the Wnt gene family in the preimplantation uterus. Increased canonical Wnt signaling in the stromal cells activated β-catenin, stimulating the production of a subset of fibroblast growth factors (FGFs) in these cells. The secreted FGFs acted in a paracrine manner via the FGF receptors in the epithelium to promote epithelial proliferation, thereby preventing differentiation of this tissue and creating a non-receptive uterus refractory to implantation. Collectively, these findings delineate a unique signaling network, involving Msx1/2, Wnts, and FGFs, which operate in the uterus at the time of implantation to control the mesenchymal-epithelial dialogue critical for successful establishment of pregnancy.
Vyšlo v časopise:
Homeobox Genes Critically Regulate Embryo Implantation by Controlling Paracrine Signaling between Uterine Stroma and Epithelium. PLoS Genet 8(2): e32767. doi:10.1371/journal.pgen.1002500
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002500
Souhrn
The mammalian Msx homeobox genes, Msx1 and Msx2, encode transcription factors that control organogenesis and tissue interactions during embryonic development. We observed overlapping expression of these factors in uterine epithelial and stromal compartments of pregnant mice prior to embryo implantation. Conditional ablation of both Msx1 and Msx2 in the uterus resulted in female infertility due to a failure in implantation. In these mutant mice (Msx1/2d/d), the uterine epithelium exhibited persistent proliferative activity and failed to attach to the embryos. Gene expression profiling of uterine epithelium and stroma of Msx1/2d/d mice revealed an elevated expression of several members of the Wnt gene family in the preimplantation uterus. Increased canonical Wnt signaling in the stromal cells activated β-catenin, stimulating the production of a subset of fibroblast growth factors (FGFs) in these cells. The secreted FGFs acted in a paracrine manner via the FGF receptors in the epithelium to promote epithelial proliferation, thereby preventing differentiation of this tissue and creating a non-receptive uterus refractory to implantation. Collectively, these findings delineate a unique signaling network, involving Msx1/2, Wnts, and FGFs, which operate in the uterus at the time of implantation to control the mesenchymal-epithelial dialogue critical for successful establishment of pregnancy.
Zdroje
1. CarsonDDBagchiIDeySKEndersACFazleabasAT 2000 Embryo Implantation. Developmental Biology 223 217 237
2. DeySKLimHDasSKReeseJPariaBC 2004 Molecular Cues to Implantation. Endocr Rev 25 341 373
3. RamathalCYBagchiICTaylorRNBagchiMK 2010 Endometrial Decidualization: Of Mice and Men. Semin Reprod Med 28 17 26
4. RubelCAJeongJ-WTsaiSYLydonJPDeMayoFJ 2010 Epithelial-Stromal Interaction and Progesterone Receptors in the Mouse Uterus. Semin Reprod Med 28 027 035
5. LeeKYJeongJ-WTsaiSYLydonJPDeMayoFJ 2007 Mouse models of implantation. Trends in Endocrinology & Metabolism 18 234 239
6. MantenaSRKannanACheonY-PLiQJohnsonPF 2006 C/EBPβ is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma. Proceedings of the National Academy of Sciences of the United States of America 103 1870 1875
7. LeeKJeongJKwakIYuC-TLanskeB 2006 Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nat Genet 38 1204 1209
8. LeeKYJeongJ-WWangJMaLMartinJF 2007 Bmp2 Is Critical for the Murine Uterine Decidual Response. Mol Cell Biol 27 5468 5478
9. KuriharaILeeD-KPetitFGJeongJLeeK 2007 COUP-TFII Mediates Progesterone Regulation of Uterine Implantation by Controlling ER Activity. PLoS Genet 3 e102 doi:10.1371/journal.pgen.0030102
10. LawsMJTaylorRNSidellNDeMayoFJLydonJP 2008 Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival. Development 135 2659 2668
11. LiQKannanADeMayoFJLydonJPCookePS 2011 The Antiproliferative Action of Progesterone in Uterine Epithelium Is Mediated by Hand2. Science 331 912 916
12. DaikokuTSongHGuoYRiesewijkAMosselmanS 2004 Uterine Msx-1 and Wnt4 Signaling Becomes Aberrant in Mice with the Loss of Leukemia Inhibitory Factor or Hoxa-10: Evidence for a Novel Cytokine-Homeobox-Wnt Signaling in Implantation. Molecular Endocrinology 18 1238 1250
13. LiQCheonYPKannanAShankerSBagchiIC 2004 A novel pathway involving progesterone receptor, 12/15-lipoxygenase-derived eicosanoids, and peroxisome proliferator-activated receptor gamma regulates implantation in mice. J Biol Chem 279 11570 11581
14. KatoSEndohHMasuhiroYKitamotoTUchiyamaS 1995 Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase. Science 270 1491 1494
15. BagchiICCheonYPLiQBagchiMK 2003 Progesterone receptor-regulated gene networks in implantation. Front Biosci 8 s852 861
16. BagchiICLiQCheonYP 2001 Role of steroid hormone-regulated genes in implantation. Ann N Y Acad Sci 943 68 76
17. PanHDengYPollardJW 2006 Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing. Proc Natl Acad Sci U S A 103 14021 14026
18. McMasterMTTengCTDeySKAndrewsGK 1992 Lactoferrin in the mouse uterus: analyses of the preimplantation period and regulation by ovarian steroids. Molecular Endocrinology 6 101 111
19. JeongJ-WLeeKYLydonJPDeMayoFJ 2006 Steroid hormone regulation of Clca3 expression in the murine uterus. Journal of Endocrinology 189 473 484
20. HuangHChuSChenY 1999 Ovarian steroids regulate 24p3 expression in mouse uterus during the natural estrous cycle and the preimplantation period. Journal of Endocrinology 162 11 19
21. SurveyorGAGendlerSJPembertonLDasSKChakrabortyI 1995 Expression and steroid hormonal control of Muc-1 in the mouse uterus. Endocrinology 136 3639 3647
22. FinnCAMartinL 1974 The control of implantation. Journal of Reproduction and Fertility 39 195 206
23. StewartCLKasparPBrunetLJBhattHGadiI 1992 Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 359 76 79
24. JeongJ-WKwakILeeKYKimTHLargeMJ 2010 Foxa2 Is Essential for Mouse Endometrial Gland Development and Fertility. Biology of Reproduction 83 396 403
25. ChenWHanB-CWangR-CXiongG-FPengJ-P Role of secretory protease inhibitor SPINK3 in mouse uterus during early pregnancy. Cell and Tissue Research 341 441 451
26. MurphyCR 2004 Uterine receptivity and the plasma membrane transformation. Cell Res 14 259 267
27. LoganCYNusseR 2004 The WNT signaling pathway in development and diseasse. Annual Review of Cell and Developmental Biology 20 781 810
28. GordonMDNusseR 2006 Wnt Signaling: Multiple Pathways, Multiple Receptors, and Multiple Transcription Factors. Journal of Biological Chemistry 281 22429 22433
29. AngersSMoonRT 2009 Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol advanced online publication
30. KawakamiYCapdevilaJBüscherDItohTEstebanCRg 2001 WNT Signals Control FGF-Dependent Limb Initiation and AER Induction in the Chick Embryo. Cell 104 891 900
31. ShimokawaTFurukawaYSakaiMLiMMiwaN 2003 Involvement of the FGF18 Gene in Colorectal Carcinogenesis, as a Novel Downstream Target of the β-Catenin/T-Cell Factor Complex. Cancer Research 63 6116 6120
32. ReinholdMINaskiMC 2007 Direct Interactions of Runx2 and Canonical Wnt Signaling Induce FGF18. Journal of Biological Chemistry 282 3653 3663
33. EswarakumarVPLaxISchlessingerJ 2005 Cellular signaling by fibroblast growth factor receptors. Cytokine & Growth Factor Reviews 16 139 149
34. BeenkenAMohammadiM 2009 The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8 235 253
35. TurnerNGroseR 2010 Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10 116 129
36. KoziczakMHolbroTHynesNE 0000 Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins. Oncogene 23 3501 3508
37. DavidsonD 1995 The function and evolution of Msx genes: pointers and paradoxes. Trends in Genetics 11 405 411
38. MaasRChenYPBeiMWooISatokataI 1996 The Role of Msx Genes in Mammalian Development. Annals of the New York Academy of Sciences 785 171 181
39. AlappatSZhangZYChenYP 2003 Msx homeobox gene family and craniofacial development. Cell Res 13 429 442
40. WangWChenXXuHLufkinT 1996 Msx3: a novel murine homologue of the Drosophila msh homeobox gene restricted to the dorsal embryonic central nervous system. Mechanisms of Development 58 203 215
41. RamosCRobertB 2005 msh/Msx gene family in neural development. Trends in Genetics 21 624 632
42. ChamorroMNSchwartzDRVonicaABrivanlouAHChoKR 2005 FGF-20 and DKK1 are transcriptional targets of [beta]-catenin and FGF-20 is implicated in cancer and development. EMBO J 24 73 84
43. ChenCSpencerTEBazerFW 2000 Fibroblast Growth Factor-10: A Stromal Mediator of Epithelial Functionin the Ovine Uterus. Biology of Reproduction 63 959 966
44. SatterfieldMCHayashiKSongGBlackSGBazerFW 2008 Progesterone Regulates FGF10, MET, IGFBP1, and IGFBP3 in the Endometrium of the Ovine Uterus. Biology of Reproduction 79 1226 1236
45. GrayCABartolFFTarletonBJWileyAAJohnsonGA 2001 Developmental Biology of Uterine Glands. Biology of Reproduction 65 1311 1323
46. JeongJWLeeHSFrancoHLBroaddusRRTaketoMM 2008 [beta]-catenin mediates glandular formation and dysregulation of [beta]-catenin induces hyperplasia formation in the murine uterus. Oncogene 28 31 40
47. FuHIshiiMGuYMaxsonR 2007 Conditional alleles of Msx1 and Msx2. genesis 45 477 481
48. SoyalSMMukherjeeALeeKYSLiJLiH 2005 Cre-mediated recombination in cell lineages that express the progesterone receptor. genesis 41 58 66
49. BigsbyRMCookePSCunhaGR 1986 A simple efficient method for separating murine uterine epithelial and mesenchymal cells. American Journal of Physiology - Endocrinology And Metabolism 251 E630 E636
50. LiQKannanAWangWDeMayoFJTaylorRN 2007 Bone Morphogenetic Protein 2 Functions via a Conserved Signaling Pathway Involving Wnt4 to Regulate Uterine Decidualization in the Mouse and the Human. Journal of Biological Chemistry 282 31725 31732
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 2
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Gene Expression and Stress Response Mediated by the Epigenetic Regulation of a Transposable Element Small RNA
- Contrasting Properties of Gene-Specific Regulatory, Coding, and Copy Number Mutations in : Frequency, Effects, and Dominance
- Homeobox Genes Critically Regulate Embryo Implantation by Controlling Paracrine Signaling between Uterine Stroma and Epithelium
- Nondisjunction of a Single Chromosome Leads to Breakage and Activation of DNA Damage Checkpoint in G2