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Cancer and Developmental Biology Laboratory (J.R.C., J.-G.C., L.H., C.L.S.), ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702; Science Applications International Corporation (T.S., L.S.), NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201
Address all correspondence and requests for reprints to: Colin L. Stewart, Laboratory of Cancer and Developmental Biology, National Cancer Institute-FCRDC, P.O. Box B, Frederick, Maryland 21702-1201. E-mail: stewartc{at}mail.ncifcrf.gov
A stage critical in mammalian development is embryo implantation. At this point, the blastocyst establishes a close interaction with the uterine tissues, a step necessary for its continued embryonic development. In many mammalian species, including man, uterine expression of the cytokine, leukemia inhibitory factor (LIF) is coincident with the onset of implantation and in mice LIF is essential to this process. The reasons for implantation failure have not been established. Here we show in LIF-deficient mice that up to the onset of implantation, changes in uterine cell proliferation, hormone levels, blastocyst localization, as well as expression of lactoferrin and Muc-1, do not differ from wild-types. However, the uterus fails to respond to the presence of embryos or to artificial stimuli by decidualizing. In mice, implantation and decidualization are induced by nidatory estrogen. We show that uterine expression of LIF is up-regulated by estrogen and LIF can replace nidatory estrogen at inducing both implantation and decidualization in ovariectomized mice. Implantation of LIF-deficient embryos in the LIF-deficient females, with normal development to term is rescued by ip injection of LIF. Transient expression of LIF on D4 of pregnancy is therefore only required to induce a state of receptivity in the uterus permitting embryo implantation and decidualization. LIF is neither required by the embryo for development nor for the maintenance of pregnancy.
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K. Tamura, T. Hara, M. Yoshie, S. Irie, A. Sobel, and H. Kogo Enhanced Expression of Uterine Stathmin during the Process of Implantation and Decidualization in Rats Endocrinology, April 1, 2003; 144(4): 1464 - 1473. [Abstract] [Full Text] [PDF]
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J.-G. Cheng and C. L. Stewart Loss of Cyclooxygenase-2 Retards Decidual Growth but Does Not Inhibit Embryo Implantation or Development to Term Biol Reprod, February 1, 2003; 68(2): 401 - 404. [Abstract] [Full Text] [PDF]
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D. G. Simmons and T. G. Kennedy Uterine Sensitization-Associated Gene-1: A Novel Gene Induced Within the Rat Endometrium at the Time of Uterine Receptivity/Sensitization for the Decidual Cell Reaction Biol Reprod, November 1, 2002; 67(5): 1638 - 1645. [Abstract] [Full Text] [PDF]
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S. Lyrakou, M.A. Hulten, and G.M. Hartshorne Growth factors promote meiosis in mouse fetal ovaries in vitro Mol. Hum. Reprod., October 1, 2002; 8(10): 906 - 911. [Abstract] [Full Text] [PDF]
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S. Curtis Hewitt, E. H. Goulding, E.M. Eddy, and K. S. Korach Studies Using the Estrogen Receptor {alpha} Knockout Uterus Demonstrate That Implantation but Not Decidualization-Associated Signaling Is Estrogen Dependent Biol Reprod, October 1, 2002; 67(4): 1268 - 1277. [Abstract] [Full Text] [PDF]
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B.A. Cork, E.M. Tuckerman, T.C. Li, and S.M. Laird Expression of interleukin (IL)-11 receptor by the human endometrium in vivo and effects of IL-11, IL-6 and LIF on the production of MMP and cytokines by human endometrial cells in vitro Mol. Hum. Reprod., September 1, 2002; 8(9): 841 - 848. [Abstract] [Full Text] [PDF]
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 J. R. A. Sherwin, S. K. Smith, A. Wilson, and A. M. Sharkey Soluble gp130 is Up-Regulated in the Implantation Window and Shows Altered Secretion in Patients with Primary Unexplained Infertility J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3953 - 3960. [Abstract] [Full Text] [PDF]
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H.-F. Chen, C.-Y. Lin, K.-H. Chao, M.-Y. Wu, Y.-S. Yang, and H.-N. Ho Defective Production of Interleukin-11 by Decidua and Chorionic Villi in Human Anembryonic Pregnancy J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2320 - 2328. [Abstract] [Full Text] [PDF]
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J.-G. Cheng, J. R. Chen, L. Hernandez, W. G. Alvord, and C. L. Stewart Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation PNAS, June 28, 2001; (2001) 151180898. [Abstract] [Full Text] [PDF]
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J.-G. Cheng, J. R. Chen, L. Hernandez, W. G. Alvord, and C. L. Stewart Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation PNAS, July 17, 2001; 98(15): 8680 - 8685. [Abstract] [Full Text] [PDF]
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