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.
Various mediators, including cytokines, growth factors, homeotic gene products, and prostaglandins (PGs), participate in the implantation process in an autocrine, paracrine, or juxtacrine manner. However, interactions among these factors that result in successful implantation are not clearly understood. Leukemia inhibitory factor (LIF), a pleiotropic cytokine, was shown to be expressed in uterine glands on day 4 morning before implantation and is critical to this process in mice. However, the mechanism by which LIF executes its effects in implantation remains unknown. Moreover, interactions of LIF with other implantation-specific molecules have not yet been defined. Using normal and delayed implantation models, we herein show that LIF is not only expressed in progesterone (P4)-primed uterine glands before implantation in response to nidatory estrogen, it is also induced in stromal cells surrounding the active blastocyst at the time of the attachment reaction. This suggests that LIF has biphasic effects: first in the preparation of the receptive uterus and subsequently in the attachment reaction. The mechanism by which LIF participates in these events was addressed using LIF-deficient mice. We observed that while uterine cell-specific proliferation, steroid hormone responsiveness, and expression patterns of several genes are normal, specific members of the EGF family of growth factors, such as amphiregulin (Ar), heparin-binding EGF-like growth factor (HB-EGF), and epiregulin, are not expressed in LIF(-/-) uteri before and during the anticipated time of implantation, although EGF receptor family members (erbBs) are expressed correctly. Furthermore, cyclooxygenase-2 (COX-2), an inducible rate-limiting enzyme for PG synthesis and essential for implantation, is aberrantly expressed in the uterus surrounding the blastocyst in LIF(-/-) mice. These results suggest that dysregulation of specific EGF-like growth factors and COX-2 in the uterus contributes, at least partially, to implantation failure in LIF(-/-) mice. Since estrogen is essential for uterine receptivity, LIF induction, and blastocyst activation, it is possible that the nidatory estrogen effects in the P4-primed uterus for implantation are mediated via LIF signaling. However, we observed that LIF can only partially resume implantation in P4-primed, delayed implanting mice in the absence of estrogen, suggesting LIF induction is one of many functions that are executed by estrogen for implantation.
Department of Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City 66160-7338, USA.
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D000818:Animals; D001755:Blastocyst; D002455:Cell Division / Q000235:genetics; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D010064:Embryo Implantation / Q000502:physiology*; D047108:Embryonic Development / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics; D047628:Estrogen Receptor alpha; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006131:Growth Inhibitors / Q000235:genetics* / Q000378:metabolism; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D015850:Interleukin-6; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D018995:Myosin Heavy Chains; D024501:Nonmuscle Myosin Type IIB; D010052:Ovariectomy; D010053:Ovary / Q000378:metabolism; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D066247:Receptor, ErbB-4; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics; D017978:Receptors, Growth Factor / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D013256:Steroids / Q000378:metabolism / Q000494:pharmacology; D014599:Uterus / Q000166:cytology / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D047628:Estrogen Receptor alpha; D016326:Extracellular Matrix Proteins; D006131:Growth Inhibitors; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D015850:Interleukin-6; D007527:Isoenzymes; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D008565:Membrane Proteins; D018995:Myosin Heavy Chains; D024501:Nonmuscle Myosin Type IIB; D011451:Prostaglandin-Endoperoxide Synthases; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D011960:Receptors, Estrogen; D017978:Receptors, Growth Factor; D011980:Receptors, Progesterone; D040262:Receptors, Vascular Endothelial Growth Factor; D013256:Steroids; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C507838:Lif protein, mouse; C092119:Hoxa10 protein, mouse; C496512:Ptgs1 protein, mouse; C587690:Erbb4 protein, mouse; C103815:nonmuscle myosin type IIB heavy chain