Control of Uterine Receptivity and Embryo Implantation by Steroid Hormone Regulation of LIF Production and LIF Receptor Activity: Towards a Molecular Understanding of “The Window of Implantation”

  • Jr-Gang Cheng
  • Clara I. Rodriguez
  • Colin L. Stewart
LIF uterus blastocyst implantation Stat MAPK 


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  1. 1.
    Finn CA. Species variation in implantation. Prog Reprod Biol 1980;7:253-261.Google Scholar
  2. 2.
    Robb L, Li R, Hartley L, Nandurkar HH, Koentgen F, Begley CG. Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nat Med 1998;4:303-308.Google Scholar
  3. 3.
    Bilinski P, Roopenian D, Gossler A. Maternal IL-llRalpha function is required for normal decidua and fetoplacental development in mice. Genes Dev 1998;12:2234-2243.Google Scholar
  4. 4.
    Cross JC, Werb Z, Fisher SJ. Implantation and the placenta: key pieces of the development puzzle. Science 1994;266:1508-1518.Google Scholar
  5. 5.
    Biggers JD. Reflections on the culture of the preimplantation embryo. Int J Dev Biol 1998;42:879-884.Google Scholar
  6. 6.
    Stewart CL, Cullinan EB. Preimplantation development of the mammalian embryo and its regulation by growth factors. Dev Genet 1997;21:91-101.Google Scholar
  7. 7.
    Bhatnagar P, Papaioannou VE, Biggers JD. CSF-1 and mouse preimplantation development in vitro. Development 1995;121:1333-1339.Google Scholar
  8. 8.
    Brison DR, Schultz RM. Apoptosis during mouse blastocyst formation: evidence for a role for survival factors including transforming growth factor alpha. Biol Reprod 1997;56:1088-1096.Google Scholar
  9. 9.
    Wuu YD, Pampfer S, Becquet P, Vanderheyden I, Lee KH, De Hertogh R. Tumor necrosis factor alpha decreases the viability of mouse blastocysts in vitro and in vivo. Biol Reprod 1999;60:479-483.Google Scholar
  10. 10.
    Finn CA, Martin L. The control of implantation. J Reprod Fertil 1974;39:195-206.Google Scholar
  11. 11.
    Kurita T, Young P, Brody JR, Lydon JP, O'Malley BW, Cunha GR. Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxy-ribonucleic acid synthesis. Endocrinology 1998;139:4708-4713.Google Scholar
  12. 12.
    Kurita T, Lee KJ, Cooke PS, Lydon JP, Cunha GR. Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus. Biol Reprod 2000;62:831-838.Google Scholar
  13. 13.
    Curtis SW, Washburn T, Sewall C, DiAugustine R, Lindzey J, Couse JF, Korach KS. Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. Proc Natl Acad Sci USA 1996;93:12626-12630.Google Scholar
  14. 14.
    Auemhammer CJ, Melmed S. Leukemia-inhibitory factor-neuroimmune modulator of endocrine function. Endocr Rev 2000;21:313-345.Google Scholar
  15. 15.
    Robinson RC, Grey LM, Staunton D, Vankelecom H, Vemallis AB, Moreau JF, Stuart DI, Heath JK, Jones EY. The crystal structure and biological function of leukemia inhibitory factor: implications for receptor binding. Cell 1994;77:1101-1116.Google Scholar
  16. 16.
    Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 1988;336:684-687.Google Scholar
  17. 17.
    Nichols J, Chambers I, Taga T, Smith A. Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines. Development 2001;128:2333-2339.Google Scholar
  18. 18.
    Bhatt H, Brunet LJ, Stewart CL. Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proc Natl A cad Sci USA 1991;88:11408-11412.Google Scholar
  19. 19.
    Shen MM, Leder P. Leukemia inhibitory factor is expressed by the preimplantation uterus and selectively blocks primitive ectoderm formation in vitro. Proc Natl Acad Sci USA 1992;89:8240-8244.Google Scholar
  20. 20.
    Chen JR, Cheng JG, Shatzer T, Sewell L, Hemandez L, Stewart CL. Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis. Endocrinology 2000;141:4365-4372.Google Scholar
  21. 21.
    Cullinan EB, Abbondanzo SJ, Anderson PS, Pollard JW, Lessey BA, Stewart CL. Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Proc Natl Acad Sci USA 1996;93:3115-3120.Google Scholar
  22. 22.
    Kholkute SD, Katkam RR, Nandedkar TD, Puri CP. Leukaemia inhibitory factor in the endometrium of the common marmoset Callithrix jacchus: localization, expression and hormonal regulation. Mol Hum Reprod 2000;6:337-343.Google Scholar
  23. 23.
    Yue ZP, Yang ZM, Wei P, Li SJ, Wang HB, Tan JH, Harper MJ. Leukemia inhibitory factor, leukemia inhibitory factor receptor, and glycoprotein 130 in rhesus monkey uterus during menstrual cycle and early pregnancy. Biol Reprod 2000;63:508-512.Google Scholar
  24. 24.
    Anegon I, Cuturi MC, Godard A, Moreau M, Terqui M, Martinat-Botte F, Soulillou JP. Presence of leukaemia inhibitory factor and interleukin 6 in porcine uterine secretions prior to conceptus attachment. Cytokine 1994;6:493-499.Google Scholar
  25. 25.
    Vogiagis D, Fry RC, Sandeman RM, Salamonsen LA. Leukaemia inhibitory factor in endometrium during the oestrous cycle, early pregnancy and in ovariectomized steroid-treated ewes. J Reprod Fertil 1997;109:279-288.Google Scholar
  26. 26.
    Yang ZM, Le SP, Chen DB, Yasukawa K, Harper MJ. Expression patterns of leukaemia inhibitory factor receptor (LIFR) and the gp130 receptor component in rabbit uterus during early pregnancy. J Reprod Fertil 1995;103:249-255.Google Scholar
  27. 27.
    Hirzel DJ, Wang J, Das SK, Dey SK, Mead RA. Changes in uterine expression of leukemia inhibitory factor during pregnancy in the Western spotted skunk. Biol Reprod 1999;60:484-492.Google Scholar
  28. 28.
    Passavant C, Zhao X, Das SK, Dey SK, Mead RA. Changes in uterine expression of leukemia inhibitory factor receptor gene during pregnancy and its up-regulation by prolactin in the western spotted skunk. Biol Reprod 2000;63:301-307.Google Scholar
  29. 29.
    Cui S, Selwood L. cDNA cloning, characterization, expression and recombinant protein production of leukemia inhibitory factor (LIF) from the marsupial, the brushtail possum (Trichosurus vulpecula). Gene 2000;243:167-178.Google Scholar
  30. 30.
    Cui S, Hope RM, Rathjen J, Voyle RB, Rathjen PD. Structure, sequence and function of a marsupial LIF gene: conservation of IL-6 family cytokines. Cytogenet Cell Genet 2001;92:271-278.Google Scholar
  31. 31.
    Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Kontgen F, Abbondanzo SJ. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor [see comments]. Nature 1992;359:76-79.Google Scholar
  32. 32.
    Vogiagis D, Salamonsen LA, Sandeman RM, Squires TJ, Butt AR, Fry RC. Effect of immunisation against leukaemia inhibitory factor on the establishment of pregnancy in sheep. Reprod Nutr Dev 1997;37:459-468.Google Scholar
  33. 33.
    Giess R, Tanasescu I, Steck T, Sendmer M. Leukaemia inhibitory factor gene mutations in infertile women. Mol Hum Reprod 1999;5:581-586.Google Scholar
  34. 34.
    Laird SM, Tuckerman EM, Dalton CF, Dunphy BC, Li TC, Zhang X. The production of leukaemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture. Hum Reprod 1997;12:569-574.Google Scholar
  35. 35.
    Psychoyos A. Endocrine control of egg implantation. In: Greep RO, Astwood EB, eds. Handbook of Physiology. Baltimore: Williams and Wilkins, 1973; 187-215.Google Scholar
  36. 36.
    Paria BC, Ma W, Tan J, Raja S, Das SK, Dey SK, Hogan BL. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proc Natl Acad Sci USA 2001;98:1047-1052.Google Scholar
  37. 37.
    Raab G, Kover K, Paria BC, Dey SK, Ezzell RM, Klagsbrun M. Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor. Development 1996;122:637-645.Google Scholar
  38. 38.
    Song H, Lim H, Das SK, Paria BC, Dey SK. Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice. Mol Endocrinol 2000;14:1147-1161.Google Scholar
  39. 39.
    Yoo HJ, Barlow DH, Mardon HJ. Temporal and spatial regulation of expression of heparin-binding epidermal growth factor-like growth factor in the human endometrium: a possible role in blastocyst implantation. Dev Genet 1997;21:102-108.Google Scholar
  40. 40.
    Lee DC. (personal comunication). 2001.Google Scholar
  41. 41.
    Ernst M, Oates A, Dunn AR. Gp130-mediated signal transduction in embryonic stem cells involves activation of Jak and Ras/mitogen-activated protein kinase pathways. J Biol Chem 1996;271:30136-30143.Google Scholar
  42. 42.
    Cheng JG, Chen JR, Hemandez L, Alvord WG, Stewart CL. Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation. Proc Natl Acad Sci USA 2001;98:8680-8685.Google Scholar
  43. 43.
    Ohtani T, Ishihara K, Atsumi T, Nishida K, Kaneko Y, Miyata T, Itoh S, Narimatsu M, Maeda H, Fukada T, Itoh M, Okano H, Hibi M, Hirano T. Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3-and SHP2-mediated signals in immune responses. Immunity 2000;12:95-105.Google Scholar
  44. 44.
    Mulac-Jericevic B, Mullinax RA, DeMayo FJ, Lydon JP, Conneely OM. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science 2000;289:1751-1754.Google Scholar
  45. 45.
    Cheng J-G, Stewart CL. (unpublished observation). 2001.Google Scholar
  46. 46.
    Paria BC, Song H, Dey SK. Implantation: molecular basis of embryo-uterine dialogue. Int J Dev Biol 2001;45:597-605.Google Scholar
  47. 47.
    Lim H, Paria BC, Das SK, Dinchuk JE, Langenbach R, Trzaskos JM, Dey SK. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 1997;91:197-208.Google Scholar
  48. 48.
    Escalante-Alcalde D, Le Stunff H, Maeda R, Hemandez L, Cheng JG, Sciorra VA, Morris AJ, Daar I, Spiegel S, L. SC. The Lipid Signaling Modulator, Phosphatidic Acid Phosphatase 2b, is required for Vasculogenesis and Axis Patterning (submitted 2002).Google Scholar
  49. 49.
    Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us Endocr Rev 1999;20:358-417.Google Scholar
  50. 50.
    Conneely OM, Lydon JP, De Mayo F, O'Malley BW. Reproductive functions of the progesterone receptor. J Soc Gynecol Investig 2000;7:525-S32.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Jr-Gang Cheng
    • 1
  • Clara I. Rodriguez
    • 1
  • Colin L. Stewart
    • 1
  1. 1.Cancer and Developmental Biology Laboratory, National Cancer Institute, Division of Basic ScienceNational Cancer Institute/Frederick Cancer Research and Development CenterFrederickUSA

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