title: Uterine Epithelial Estrogen Receptor-α Controls Decidualization via a Paracrine Mechanism.
abstract: Steroid hormone-regulated differentiation of uterine stromal cells, known as decidualization, is essential for embryo implantation. The role of the estrogen receptor-α (ESR1) during this differentiation process is unclear. Development of conditional Esr1-null mice showed that deletion of this gene in both epithelial and stromal compartments of the uterus leads to a complete blockade of decidualization, indicating a critical role of ESR1 during this process. To further elucidate the cell type-specific function of ESR1 in the uterus, we created WE(d/d) mice in which Esr1 is ablated in uterine luminal and glandular epithelia but is retained in the stroma. Uteri of WE(d/d) mice failed to undergo decidualization, indicating that epithelial ESR1 contributes to stromal differentiation via a paracrine mechanism. We noted markedly reduced production of the leukemia inhibitory factor (LIF) in WE(d/d) uteri. Supplementation with LIF restored decidualization in WE(d/d) mice. Our study indicated that LIF acts synergistically with progesterone to induce the expression of Indian hedgehog (IHH) in uterine epithelium and its receptor patched homolog 1 in the stroma. IHH then induces the expression of chicken ovalbumin upstream promoter-transcription factor II, a transcription factor that promotes stromal differentiation. To address the mechanism by which LIF induces IHH expression, we used mice lacking uterine epithelial signal transducer and activator of transcription 3, a well-known mediator of LIF signaling. Our study revealed that LIF-mediated induction of IHH occurs without the activation of epithelial signal transducer and activator of transcription 3 but uses an alternate pathway involving the activation of the ERK1/2 kinase. Collectively our results provide unique insights into the paracrine mechanisms by which ESR1 directs epithelial-stromal dialogue during pregnancy establishment.
authors.affiliation: Departments of Molecular and Integrative Physiology (S.P., M.K.B.) and Comparative Biosciences (M.J.L., I.C.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
authors.forename: S
authors.initials: S
authors.lastname: Pawar
authors.affiliation: Departments of Molecular and Integrative Physiology (S.P., M.K.B.) and Comparative Biosciences (M.J.L., I.C.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
authors.forename: M J
authors.initials: MJ
authors.lastname: Laws
authors.affiliation: Departments of Molecular and Integrative Physiology (S.P., M.K.B.) and Comparative Biosciences (M.J.L., I.C.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
authors.forename: I C
authors.initials: IC
authors.lastname: Bagchi
authors.affiliation: Departments of Molecular and Integrative Physiology (S.P., M.K.B.) and Comparative Biosciences (M.J.L., I.C.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
authors.forename: M K
authors.initials: MK
authors.lastname: Bagchi
mesh_terms: D000818:Animals; D051837:COUP Transcription Factor II / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D003656:Decidua / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D010064:Embryo Implantation / Q000502:physiology*; D004789:Enzyme Activation / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D053823:Hedgehog Proteins / Q000096:biosynthesis; D053605:Leukemia Inhibitory Factor / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000166:cytology / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051837:COUP Transcription Factor II; D047628:Estrogen Receptor alpha; D053823:Hedgehog Proteins; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C514061:ihh protein, mouse; D011374:Progesterone; D048049:Extracellular Signal-Regulated MAP Kinases