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The Epidermal Growth Factor Receptor Critically Regulates Endometrial Function during Early Pregnancy


Approximately 10% of reproductive aged women are considered infertile. While great strides have been made in assisted reproductive technologies, overall success rates, especially considering the cost, remain low. Studies indicate that due to its sequential nature, nearly 75% of pregnancy failures are due to defects that occur very early in gestation. Therefore, understanding the physiological changes that occur in the endometrium during this period and how those changes are regulated is of paramount importance if we are to improve our ability to address female reproductive health concerns. We investigated a family of growth factor receptors and identified one that critically regulates the growth and survival of the endometrium in response to the implanting embryo. Furthermore, we used unbiased approaches to identify which signaling pathways and genetic networks are activated downstream of this receptor to execute each of the processes necessary for a successful pregnancy. Understanding the mechanisms and genetic networks with which pregnancy is regulated is a prerequisite to the development of effective pharmaceutical therapeutics.


Vyšlo v časopise: The Epidermal Growth Factor Receptor Critically Regulates Endometrial Function during Early Pregnancy. PLoS Genet 10(6): e32767. doi:10.1371/journal.pgen.1004451
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004451

Souhrn

Approximately 10% of reproductive aged women are considered infertile. While great strides have been made in assisted reproductive technologies, overall success rates, especially considering the cost, remain low. Studies indicate that due to its sequential nature, nearly 75% of pregnancy failures are due to defects that occur very early in gestation. Therefore, understanding the physiological changes that occur in the endometrium during this period and how those changes are regulated is of paramount importance if we are to improve our ability to address female reproductive health concerns. We investigated a family of growth factor receptors and identified one that critically regulates the growth and survival of the endometrium in response to the implanting embryo. Furthermore, we used unbiased approaches to identify which signaling pathways and genetic networks are activated downstream of this receptor to execute each of the processes necessary for a successful pregnancy. Understanding the mechanisms and genetic networks with which pregnancy is regulated is a prerequisite to the development of effective pharmaceutical therapeutics.


Zdroje

1. WilcoxAJ, WeinbergCR, O'ConnorJF, BairdDD, SchlattererJP, et al. (1988) Incidence of early loss of pregnancy. N Engl J Med 319: 189–194.

2. ZinamanMJ, CleggED, BrownCC, O'ConnorJ, SelevanSG (1996) Estimates of human fertility and pregnancy loss. Fertil Steril 65: 503–509.

3. WangX, ChenC, WangL, ChenD, GuangW, et al. (2003) Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril 79: 577–584.

4. BoivinJ, BuntingL, CollinsJA, NygrenKG (2007) International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod 22: 1506–1512.

5. WangH, DeySK (2006) Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet 7: 185–199.

6. ChaJ, SunX, DeySK (2012) Mechanisms of implantation: strategies for successful pregnancy. Nat Med 18: 1754–1767.

7. MacklonNS, GeraedtsJP, FauserBC (2002) Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Hum Reprod Update 8: 333–343.

8. StephensonMD, AwartaniKA, RobinsonWP (2002) Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study. Hum Reprod 17: 446–451.

9. PhilippT, PhilippK, ReinerA, BeerF, KalousekDK (2003) Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum Reprod 18: 1724–1732.

10. RaiR, ReganL (2006) Recurrent miscarriage. Lancet 368: 601–611.

11. JauniauxE, FarquharsonRG, ChristiansenOB, ExaltoN (2006) Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 21: 2216–2222.

12. Practice Committee of the American Society for Reproductive M (2012) Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 98: 1103–1111.

13. MaWG, SongH, DasSK, PariaBC, DeySK (2003) Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. Proc Natl Acad Sci U S A 100: 2963–2968.

14. LargeMJ, DeMayoFJ (2012) The regulation of embryo implantation and endometrial decidualization by progesterone receptor signaling. Mol Cell Endocrinol 358: 155–165.

15. LydonJP, DeMayoFJ, FunkCR, ManiSK, HughesAR, et al. (1995) Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9: 2266–2278.

16. LeeK, JeongJ, KwakI, YuCT, LanskeB, et al. (2006) Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nat Genet 38: 1204–1209.

17. KuriharaI, LeeDK, PetitFG, JeongJ, LeeK, et al. (2007) COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity. PLoS Genet 3: e102.

18. FrancoHL, LeeKY, BroaddusRR, WhiteLD, LanskeB, et al. (2010) Ablation of Indian hedgehog in the murine uterus results in decreased cell cycle progression, aberrant epidermal growth factor signaling, and increased estrogen signaling. Biol Reprod 82: 783–790.

19. DasSK, DasN, WangJ, LimH, SchryverB, et al. (1997) Expression of betacellulin and epiregulin genes in the mouse uterus temporally by the blastocyst solely at the site of its apposition is coincident with the “window” of implantation. Dev Biol 190: 178–190.

20. TamadaH, DasSK, AndrewsGK, DeySK (1991) Cell-type-specific expression of transforming growth factor-alpha in the mouse uterus during the peri-implantation period. Biol Reprod 45: 365–372.

21. DasSK, ChakrabortyI, PariaBC, WangXN, PlowmanG, et al. (1995) Amphiregulin is an implantation-specific and progesterone-regulated gene in the mouse uterus. Mol Endocrinol 9: 691–705.

22. DasSK, WangXN, PariaBC, DammD, AbrahamJA, et al. (1994) Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation. Development 120: 1071–1083.

23. RaabG, KoverK, PariaBC, DeySK, EzzellRM, et al. (1996) Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor. Development 122: 637–645.

24. TanY, LiM, CoxS, DavisMK, TawfikO, et al. (2004) HB-EGF directs stromal cell polyploidy and decidualization via cyclin D3 during implantation. Dev Biol 265: 181–195.

25. XieH, WangH, TranguchS, IwamotoR, MekadaE, et al. (2007) Maternal heparin-binding-EGF deficiency limits pregnancy success in mice. Proc Natl Acad Sci U S A 104: 18315–18320.

26. LuettekeNC, QiuTH, FentonSE, TroyerKL, RiedelRF, et al. (1999) Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development 126: 2739–2750.

27. ThreadgillDW, DlugoszAA, HansenLA, TennenbaumT, LichtiU, et al. (1995) Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269: 230–234.

28. LeeKF, SimonH, ChenH, BatesB, HungMC, et al. (1995) Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378: 394–398.

29. RiethmacherD, Sonnenberg-RiethmacherE, BrinkmannV, YamaaiT, LewinGR, et al. (1997) Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389: 725–730.

30. GassmannM, CasagrandaF, OrioliD, SimonH, LaiC, et al. (1995) Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378: 390–394.

31. SibiliaM, WagnerEF (1995) Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269: 234–238.

32. MiettinenPJ, BergerJE, MenesesJ, PhungY, PedersenRA, et al. (1995) Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376: 337–341.

33. DasSK, TsukamuraH, PariaBC, AndrewsGK, DeySK (1994) Differential expression of epidermal growth factor receptor (EGF-R) gene and regulation of EGF-R bioactivity by progesterone and estrogen in the adult mouse uterus. Endocrinology 134: 971–981.

34. LimH, DeySK, DasSK (1997) Differential expression of the erbB2 gene in the periimplantation mouse uterus: potential mediator of signaling by epidermal growth factor-like growth factors. Endocrinology 138: 1328–1337.

35. LimH, DasSK, DeySK (1998) erbB genes in the mouse uterus: cell-specific signaling by epidermal growth factor (EGF) family of growth factors during implantation. Dev Biol 204: 97–110.

36. TidcombeH, Jackson-FisherA, MathersK, SternDF, GassmannM, et al. (2003) Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality. Proc Natl Acad Sci U S A 100: 8281–8286.

37. LeeTC, ThreadgillDW (2009) Generation and validation of mice carrying a conditional allele of the epidermal growth factor receptor. Genesis 47: 85–92.

38. CroneSA, ZhaoYY, FanL, GuY, MinamisawaS, et al. (2002) ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8: 459–465.

39. LeeD, YuM, LeeE, KimH, YangY, et al. (2009) Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium. J Clin Invest 119: 2702–2713.

40. SoyalSM, MukherjeeA, LeeKY, LiJ, LiH, et al. (2005) Cre-mediated recombination in cell lineages that express the progesterone receptor. Genesis 41: 58–66.

41. NelsonKG, TakahashiT, BossertNL, WalmerDK, McLachlanJA (1991) Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation. Proc Natl Acad Sci U S A 88: 21–25.

42. MellorSJ, ThomasEJ (1995) Interactions between oestradiol and epidermal growth factor in endometrial stromal proliferation and differentiation. J Reprod Fertil 104: 157–164.

43. TongW, PollardJW (1999) Progesterone inhibits estrogen-induced cyclin D1 and cdk4 nuclear translocation, cyclin E- and cyclin A-cdk2 kinase activation, and cell proliferation in uterine epithelial cells in mice. Mol Cell Biol 19: 2251–2264.

44. LiQ, KannanA, WangW, DemayoFJ, TaylorRN, et al. (2007) Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human. J Biol Chem 282: 31725–31732.

45. LeeKY, JeongJW, WangJ, MaL, MartinJF, et al. (2007) Bmp2 is critical for the murine uterine decidual response. Mol Cell Biol 27: 5468–5478.

46. FrancoHL, DaiD, LeeKY, RubelCA, RoopD, et al. (2011) WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse. FASEB J 25: 1176–1187.

47. Huang daW, ShermanBT, LempickiRA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57.

48. Huang daW, ShermanBT, LempickiRA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37: 1–13.

49. KesslerCA, SchroederJK, BrarAK, HandwergerS (2006) Transcription factor ETS1 is critical for human uterine decidualization. Mol Hum Reprod 12: 71–76.

50. GellersenB, BrosensIA, BrosensJJ (2007) Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med 25: 445–453.

51. HomYK, YoungP, WiesenJF, MiettinenPJ, DerynckR, et al. (1998) Uterine and vaginal organ growth requires epidermal growth factor receptor signaling from stroma. Endocrinology 139: 913–921.

52. Ignar-TrowbridgeDM, NelsonKG, BidwellMC, CurtisSW, WashburnTF, et al. (1992) Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor. Proc Natl Acad Sci U S A 89: 4658–4662.

53. ClementiC, TripuraniSK, LargeMJ, EdsonMA, CreightonCJ, et al. (2013) Activin-Like Kinase 2 Functions in Peri-implantation Uterine Signaling in Mice and Humans. PLoS Genet 9: e1003863.

54. NagashimaT, LiQ, ClementiC, LydonJP, DeMayoFJ, et al. (2013) BMPR2 is required for postimplantation uterine function and pregnancy maintenance. J Clin Invest 123: 2539–2550.

55. HayashiK, EriksonDW, TilfordSA, BanyBM, MacleanJA2nd, et al. (2009) Wnt genes in the mouse uterus: potential regulation of implantation. Biol Reprod 80: 989–1000.

56. JeongJW, LeeHS, FrancoHL, BroaddusRR, TaketoMM, et al. (2009) beta-catenin mediates glandular formation and dysregulation of beta-catenin induces hyperplasia formation in the murine uterus. Oncogene 28: 31–40.

57. MericskayM, KitajewskiJ, SassoonD (2004) Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus. Development 131: 2061–2072.

58. MillerC, SassoonDA (1998) Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract. Development 125: 3201–3211.

59. VainioS, HeikkilaM, KispertA, ChinN, McMahonAP (1999) Female development in mammals is regulated by Wnt-4 signalling. Nature 397: 405–409.

60. RichardsRG, BrarAK, FrankGR, HartmanSM, JikiharaH (1995) Fibroblast cells from term human decidua closely resemble endometrial stromal cells: induction of prolactin and insulin-like growth factor binding protein-1 expression. Biol Reprod 52: 609–615.

61. RubelCA, LanzRB, KommaganiR, FrancoHL, LydonJP, et al. (2012) Research resource: Genome-wide profiling of progesterone receptor binding in the mouse uterus. Mol Endocrinol 26: 1428–1442.

62. CohenP (2002) Protein kinases–the major drug targets of the twenty-first century? Nat Rev Drug Discov 1: 309–315.

63. MaruyamaT, YoshimuraY, YodoiJ, SabeH (1999) Activation of c-Src kinase is associated with in vitro decidualization of human endometrial stromal cells. Endocrinology 140: 2632–2636.

64. GambaG (2005) Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension. Am J Physiol Renal Physiol 288: F245–252.

65. XuBE, StippecS, ChuPY, LazrakA, LiXJ, et al. (2005) WNK1 activates SGK1 to regulate the epithelial sodium channel. Proc Natl Acad Sci U S A 102: 10315–10320.

66. RuanYC, GuoJH, LiuX, ZhangR, TsangLL, et al. (2012) Activation of the epithelial Na+ channel triggers prostaglandin E(2) release and production required for embryo implantation. Nat Med 18: 1112–1117.

67. XuBE, StippecS, LenertzL, LeeBH, ZhangW, et al. (2004) WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. J Biol Chem 279: 7826–7831.

68. VerissimoF, JordanP (2001) WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. Oncogene 20: 5562–5569.

69. ManningG, WhyteDB, MartinezR, HunterT, SudarsanamS (2002) The protein kinase complement of the human genome. Science 298: 1912–1934.

70. XuB, EnglishJM, WilsbacherJL, StippecS, GoldsmithEJ, et al. (2000) WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II. J Biol Chem 275: 16795–16801.

71. DissanayakeVH, TowerC, BroderickA, StockerLJ, SeneviratneHR, et al. (2007) Polymorphism in the epidermal growth factor gene is associated with birthweight in Sinhalese and white Western Europeans. Mol Hum Reprod 13: 425–429.

72. FujitaY, KurachiH, MorishigeK, AmemiyaK, TerakawaN, et al. (1991) Decrease in epidermal growth factor receptor and its messenger ribonucleic acid levels in intrauterine growth-retarded and diabetes mellitus-complicated pregnancies. J Clin Endocrinol Metab 72: 1340–1345.

73. FondacciC, AlsatE, GabrielR, BlotP, NessmannC, et al. (1994) Alterations of human placental epidermal growth factor receptor in intrauterine growth retardation. J Clin Invest 93: 1149–1155.

74. GabrielR, AlsatE, Evain-BrionD (1994) Alteration of epidermal growth factor receptor in placental membranes of smokers: relationship with intrauterine growth retardation. Am J Obstet Gynecol 170: 1238–1243.

75. BrysM, SemczukA, RechbergerT, KrajewskaWM (2007) Expression of erbB-1 and erbB-2 genes in normal and pathological human endometrium. Oncol Rep 18: 261–265.

76. KonecnyGE, SantosL, WinterhoffB, HatmalM, KeeneyGL, et al. (2009) HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer. Br J Cancer 100: 89–95.

77. LebovicDI, BaldocchiRA, MuellerMD, TaylorRN (2002) Altered expression of a cell-cycle suppressor gene, Tob-1, in endometriotic cells by cDNA array analyses. Fertil Steril 78: 849–854.

78. BurneyRO, TalbiS, HamiltonAE, VoKC, NyegaardM, et al. (2007) Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 148: 3814–3826.

79. FinnCA, MartinL (1972) Endocrine control of the timing of endometrial sensitivity to a decidual stimulus. Biol Reprod 7: 82–86.

80. MarkoffE, ZeitlerP, PelegS, HandwergerS (1983) Characterization of the synthesis and release of prolactin by an enriched fraction of human decidual cells. J Clin Endocrinol Metab 56: 962–968.

81. HartigSM, HeB, NewbergJY, OchsnerSA, LooseDS, et al. (2012) Feed-forward inhibition of androgen receptor activity by glucocorticoid action in human adipocytes. Chem Biol 19: 1126–1141.

82. HartigSM, NewbergJY, BoltMJ, SzafranAT, MarcelliM, et al. (2011) Automated microscopy and image analysis for androgen receptor function. Methods Mol Biol 776: 313–331.

83. SzafranAT, SzwarcM, MarcelliM, ManciniMA (2008) Androgen receptor functional analyses by high throughput imaging: determination of ligand, cell cycle, and mutation-specific effects. PLoS One 3: e3605.

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Genetika Reprodukčná medicína

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PLOS Genetics


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