INTERACTION BETWEEN BLASTOCYST AND UTERINE ENDOMETRIUM

Summary

Principal Investigator: ROBERT MICHAEL ROBERTS
Abstract: Early pregnancy loss is a feature of all mammals and is particularly high in women. It is a major public health concern. More than 50% of normally conceived pregnancies fail in the period at about the time the embryo attaches to the uterus and begins to implant. Among the causes are developmental abnormalities of the embryo, weak or late signaling from the trophectoderm (the precursor of the placenta) and an ill- prepared maternal uterus. Here we shall study two aspects of conceptus-maternal relationship in early pregnancy. The first (goal 1) is to define the role of the transcription factor Cdx2 in trophectoderm specification and functional differentiation. Aim 1A is to confirm that Cdx2 plays a key role in the transcriptional control of the genes for the signaling molecule interferon-tau (IFN-T) and other genes characteristically up-regulated in trophectoderm. Aim 1B will test the hypothesis that Cdx2 is necessary in directing trophectoderm emergence in murine and bovine embryos and in maintaining a polarized epithelium. Aim 1C will confirm preliminary studies that Cdx2 is a marker of presumptive trophectoderm as early as the 2-cell stage of development. We shall also determine whether it is an analogous marker of cell fate in the bovine embryo. Goal 2 of this project is to define the function of Sin1, a newly discovered protein that associates with carboxyl end of the cytoplasmic domain of the IFN receptor subunit, IFNAR2. We hypothesize that maternal recognition of pregnancy involves a localized inflammatory response and the modulation of stress pathways in maternal endometrium at the site of implantation, and that Sin1 links the IFN response pathway to signal transduction pathways, including the stress-activated protein kinase (SAPK) pathway. Aim 2A is to define partners for Sin1 in endometrial signaling through the use of a yeast two-hybrid screen. Aim 2B will test the hypothesis that when IFN-T binds to the cell surface of uterine epithelial cells Sin 1 will be recruited, and this event will precede changes in the activities of stress-activated signal transduction pathways. Aim 2C will examine whether there is cellular relocation of Sin1 following IFN-T binding to the cell. Aim 2D will attempt to knock down Sin1 expression by RNAi and, by using this approach, determine whether Sin1 plays a role in some of the varied (pleiotropic) actions of type I IFN on mammalian cells. Aim 2E will explore whether the over-expression of different domains of the Sin1 protein can interfere with normal Sin1 function. Aim 2F is to create Sin1 null mice in order to gain a more complete insight into Sin1 function in the whole animal as well as in uterine endometrium. Together these studies are expected to provide information on two key events in early pregnancy, the formation of an early placenta and immediate maternal responses to the presence of a tiny embryo attaching to her uterine wall.
Funding Period: ----------------1986 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Cdx2 gene expression and trophectoderm lineage specification in mouse embryos
    Kaushik Deb
    Department of Animal Sciences, Columbia, MO 65211, USA
    Science 311:992-6. 2006
  2. pmc Effect of maternal obesity on estrous cyclicity, embryo development and blastocyst gene expression in a mouse model
    Pablo Bermejo-Alvarez
    Bond Life Sciences Center, University of Missouri, 263a Life Sciences Center, 1201 Rollins St, Columbia, MO 65211, USA
    Hum Reprod 27:3513-22. 2012
  3. doi Porcine induced pluripotent stem cells analogous to naïve and primed embryonic stem cells of the mouse
    Bhanu Prakash V L Telugu
    Division of Animal Sciences, University of Missouri, Columbia, MO, USA
    Int J Dev Biol 54:1703-11. 2010
  4. pmc Effects of fgf2 and oxygen in the bmp4-driven differentiation of trophoblast from human embryonic stem cells
    Padmalaya Das
    Department of Animal Sciences, University of Missouri Columbia, Christopher S Bond Life Sciences Center, 65211, USA
    Stem Cell Res 1:61-74. 2007
  5. doi The role of homeobox protein distal-less 3 and its interaction with ETS2 in regulating bovine interferon-tau gene expression-synergistic transcriptional activation with ETS2
    Toshihiko Ezashi
    Department of Animal Sciences, University of Missouri, Columbia, Missouri 65211, USA
    Biol Reprod 79:115-24. 2008
  6. pmc Human embryonic stem cells as models for trophoblast differentiation
    L C Schulz
    Division of Animal Sciences, University of Missouri Columbia, Columbia, MO 65211, USA
    Placenta 29:S10-6. 2008
  7. pmc Interferons and the maternal-conceptus dialog in mammals
    R Michael Roberts
    Department of Animal Sciences, University of Missouri, Columbia, MO 65211, USA
    Semin Cell Dev Biol 19:170-7. 2008
  8. pmc Interferon-tau, a Type 1 interferon involved in maternal recognition of pregnancy
    R Michael Roberts
    Department of Animal Sciences, University of Missouri Columbia, 240B CS Bond Life Sciences Center, 1201 Rollins Street, Columbia, MO 65211, United States
    Cytokine Growth Factor Rev 18:403-8. 2007
  9. ncbi Effect of interferon-tau administration on endometrium of nonpregnant ewes: a comparison with pregnant ewes
    Yizhen Chen
    Department of Animal Sciences, University of Missouri, Columbia, 65211, USA
    Endocrinology 147:2127-37. 2006
  10. ncbi Origin and evolution of the TKDP gene family
    Anindita Chakrabarty
    Department of Veterinary Pathobiology, University of Missouri Columbia, Columbia, MO 65211, USA
    Gene 373:35-43. 2006

Scientific Experts

  • ROBERT MICHAEL ROBERTS
  • L C Schulz
  • Bhanu Prakash V L Telugu
  • Angela M Walker
  • Toshihiko Ezashi
  • Anindita Chakrabarty
  • Padmalaya Das
  • Mika Katayama
  • Yizhen Chen
  • Jonathan A Green
  • Pablo Bermejo-Alvarez
  • Liang Zhou
  • Cheryl S Rosenfeld
  • Rangan Gupta
  • Leonard B Hearne
  • Eric Antoniou
  • Kaushik Deb
  • Henry J Kaplan
  • Haruyo Matsuyama
  • Douglas C Dean
  • Yongqing Liu
  • Wei Wang
  • Juan Fernandez de Castro
  • Mark R Ellersieck
  • Sunilima Sinha
  • Andrei P Alexenko
  • Shrikesh Sachdev
  • Suzanne D Westfall
  • Kimberly A Livingston
  • Zhilin Liu
  • Michael R Roberts
  • Austin L Hughes
  • Mayandi Sivaguru
  • Nagappan Mathialagan
  • Hwan Yul Yong
  • Mary P Avalle
  • James A Maclean
  • Alan D Ealy

Detail Information

Publications28

  1. ncbi Cdx2 gene expression and trophectoderm lineage specification in mouse embryos
    Kaushik Deb
    Department of Animal Sciences, Columbia, MO 65211, USA
    Science 311:992-6. 2006
    ..The asymmetrical distribution of Cdx2 gene products in the oocyte and embryo defines the lineage to trophectoderm...
  2. pmc Effect of maternal obesity on estrous cyclicity, embryo development and blastocyst gene expression in a mouse model
    Pablo Bermejo-Alvarez
    Bond Life Sciences Center, University of Missouri, 263a Life Sciences Center, 1201 Rollins St, Columbia, MO 65211, USA
    Hum Reprod 27:3513-22. 2012
    ..Does maternal obesity affect estrous cyclicity, embryo development and blastocyst gene expression in mice?..
  3. doi Porcine induced pluripotent stem cells analogous to naïve and primed embryonic stem cells of the mouse
    Bhanu Prakash V L Telugu
    Division of Animal Sciences, University of Missouri, Columbia, MO, USA
    Int J Dev Biol 54:1703-11. 2010
    ..They exhibit high telomerase activity, a short cell cycle interval, and a normal karyotype, and are able to generate teratomas. Currently, the competence of these lines for contributing to germ-line chimeras is being tested...
  4. pmc Effects of fgf2 and oxygen in the bmp4-driven differentiation of trophoblast from human embryonic stem cells
    Padmalaya Das
    Department of Animal Sciences, University of Missouri Columbia, Christopher S Bond Life Sciences Center, 65211, USA
    Stem Cell Res 1:61-74. 2007
    ..In conclusion, BMP4 induced conversion of hESC exclusively towards trophoblast; FGF2 slowed differentiation, while O(2) accelerated this process and promoted syncytiotrophoblast formation...
  5. doi The role of homeobox protein distal-less 3 and its interaction with ETS2 in regulating bovine interferon-tau gene expression-synergistic transcriptional activation with ETS2
    Toshihiko Ezashi
    Department of Animal Sciences, University of Missouri, Columbia, Missouri 65211, USA
    Biol Reprod 79:115-24. 2008
    ..Together, these results suggest that DLX3 has a central role in controlling IFNT gene expression by associating with ETS2 on the IFNT promoter...
  6. pmc Human embryonic stem cells as models for trophoblast differentiation
    L C Schulz
    Division of Animal Sciences, University of Missouri Columbia, Columbia, MO 65211, USA
    Placenta 29:S10-6. 2008
    ..Immunohistochemical observations performed on whole colonies combined with microarray analysis of mRNA can be employed to track developmental transitions as they occur over time and in two-dimensional space as the cells respond to BMP4...
  7. pmc Interferons and the maternal-conceptus dialog in mammals
    R Michael Roberts
    Department of Animal Sciences, University of Missouri, Columbia, MO 65211, USA
    Semin Cell Dev Biol 19:170-7. 2008
    ..Conceivably, disparate signaling mechanisms trigger common downstream events necessary to secure a successful pregnancy...
  8. pmc Interferon-tau, a Type 1 interferon involved in maternal recognition of pregnancy
    R Michael Roberts
    Department of Animal Sciences, University of Missouri Columbia, 240B CS Bond Life Sciences Center, 1201 Rollins Street, Columbia, MO 65211, United States
    Cytokine Growth Factor Rev 18:403-8. 2007
    ..The IFNT provide an illustration of how a gene control region can be commandeered and then refined to provide a radically changed pattern of expression...
  9. ncbi Effect of interferon-tau administration on endometrium of nonpregnant ewes: a comparison with pregnant ewes
    Yizhen Chen
    Department of Animal Sciences, University of Missouri, Columbia, 65211, USA
    Endocrinology 147:2127-37. 2006
    ..IFNT treatment mimics pregnancy, but relatively high doses of im-injected IFNT are required to elicit a full endometrial response...
  10. ncbi Origin and evolution of the TKDP gene family
    Anindita Chakrabarty
    Department of Veterinary Pathobiology, University of Missouri Columbia, Columbia, MO 65211, USA
    Gene 373:35-43. 2006
    ..The TKDPs provide an example of a gene family that is evolving rapidly by whole gene duplication, intragenic duplication events, and selection for amino acid (aa) change...
  11. ncbi Rapid evolution of the trophoblast kunitz domain proteins (TKDPs)-a multigene family in ruminant ungulates
    Anindita Chakrabarty
    Department of Veterinary Pathobiology, University of Missouri Columbia, Columbia, Missouri 65211, USA
    J Mol Evol 63:274-82. 2006
    ....
  12. pmc Ets-2 and C/EBP-beta are important mediators of ovine trophoblast Kunitz domain protein-1 gene expression in trophoblast
    Anindita Chakrabarty
    Departments of Veterinary Pathobiology, University of Missouri Columbia, Columbia, MO 65211, USA
    BMC Mol Biol 8:14. 2007
    ..Our goal here has been to determine whether the ovine (ov) Tkdp-1 and IFNT genes possess a similar transcriptional code...
  13. pmc Combinatorial roles of protein kinase A, Ets2, and 3',5'-cyclic-adenosine monophosphate response element-binding protein-binding protein/p300 in the transcriptional control of interferon-tau expression in a trophoblast cell line
    Padmalaya Das
    Christopher S Bond Life Sciences Center, University of Missouri Columbia, 1201 East Rollins Street, Columbia, MO 65211 7310, USA
    Mol Endocrinol 22:331-43. 2008
    ..The up-regulation of IFNT in the elongating bovine conceptus is likely due to the combinatorial effects of PKA, Ets2, and CBP/p300 and triggered via growth factors released from maternal endometrium...
  14. ncbi A microarray analysis for genes regulated by interferon-tau in ovine luminal epithelial cells
    Yizhen Chen
    Division of Animal Sciences, University of Missouri Columbia, Missouri 65211, USA
    Reproduction 134:123-35. 2007
    ..IFNT targets a complex range of physiological processes during the establishment of pregnancy...
  15. pmc Characterization of the bovine type I IFN locus: rearrangements, expansions, and novel subfamilies
    Angela M Walker
    Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA
    BMC Genomics 10:187. 2009
    ....
  16. pmc Derivation of induced pluripotent stem cells from pig somatic cells
    Toshihiko Ezashi
    Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA
    Proc Natl Acad Sci U S A 106:10993-8. 2009
    ..Such cell lines derived from individual animals could provide a means for testing the safety and efficacy of stem cell-derived tissue grafts when returned to the same pigs at a later age...
  17. ncbi Induced pluripotent stem cells from swine (Sus scrofa): why they may prove to be important
    R Michael Roberts
    Division of Animal Sciences, University of Missouri, Columbia, MO, USA
    Cell Cycle 8:3078-81. 2009
    ....
  18. doi The promise of stem cell research in pigs and other ungulate species
    Bhanu Prakash V L Telugu
    Division of Animal Sciences, Christopher S Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA
    Stem Cell Rev 6:31-41. 2010
    ....
  19. pmc Development of monozygotic twin mouse embryos from the time of blastomere separation at the two-cell stage to blastocyst
    Mika Katayama
    Division of Animal Sciences, and Christopher S Bond Life Sciences Center, University of Missouri, 1201 E Rollins Street, Columbia, MO 65211, USA
    Biol Reprod 82:1237-47. 2010
    ..These data could explain the difficulty of creating monozygotic twins from two-cell stage embryos...
  20. doi The effect of superovulation on the contributions of individual blastomeres from 2-cell stage CF1 mouse embryos to the blastocyst
    Mika Katayama
    Division of Animal Sciences, Christopher S Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
    Int J Dev Biol 54:675-81. 2010
    ..In CF1 mice, superovulation has little effect on development to blastocyst, but enforces a greater degree of lineage restriction than natural breeding, most likely through constraints imposed by the zona pellucida...
  21. pmc Transcript profiling of individual twin blastomeres derived by splitting two-cell stage murine embryos
    R Michael Roberts
    Division of Animal Sciences, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
    Biol Reprod 84:487-94. 2011
    ....
  22. pmc Trophoblast stem cells
    R Michael Roberts
    Division of Animal Sciences, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
    Biol Reprod 84:412-21. 2011
    ..Recent derivation of TSC from blastocysts of the rhesus monkey suggests that isolation of the human equivalents may be possible and will reveal the extent to which mechanisms uncovered by using animal models are true in our own species...
  23. pmc Expression of bovine interferon-tau variants according to sex and age of conceptuses
    Angela M Walker
    Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA
    Theriogenology 72:44-53. 2009
    ..001) among conceptuses of different age, although two, representing boIFN1a and boIFN3c, predominated throughout development. Notably, no alteration in overall IFNT variant diversity was detected in CT-1 cells over time (P=0.124)...
  24. pmc Dynamic changes in leptin distribution in the progression from ovum to blastocyst of the pre-implantation mouse embryo
    Laura C Schulz
    Department of Obstetrics, Gynecology and Women s Health, N625A Health Sciences Center, 1 Hospital Drive, Columbia, Missouri 65212, USA
    Reproduction 141:767-77. 2011
    ....
  25. pmc Differentiation of induced pluripotent stem cells of swine into rod photoreceptors and their integration into the retina
    Liang Zhou
    Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People s Republic of China
    Stem Cells 29:972-80. 2011
    ....
  26. pmc Leukemia inhibitory factor (LIF)-dependent, pluripotent stem cells established from inner cell mass of porcine embryos
    Bhanu Prakash V L Telugu
    Division of Animal Sciences, University of Missouri, Columbia, Missouri 65211 7310, USA
    J Biol Chem 286:28948-53. 2011
    ....
  27. pmc Generation of colonies of induced trophoblast cells during standard reprogramming of porcine fibroblasts to induced pluripotent stem cells
    Toshihiko Ezashi
    Bond Life Sciences Center and Division of Animal Sciences, University of Missouri, Columbia, Missouri, USA
    Biol Reprod 85:779-87. 2011
    ..In conclusion, reprogramming of porcine fibroblasts to iPS cells generates, as a by-product, colonies composed of self-renewing populations of TR cells, possibly containing TR stem cells...
  28. pmc Effect of leptin on mouse trophoblast giant cells
    L C Schulz
    Division of Animal Sciences, University of Missouri, Columbia, Missouri 65211, USA
    Biol Reprod 80:415-24. 2009
    ..The data suggest that leptin accelerates disappearance of non-giant cells while inhibiting terminal differentiation of committed giant cells, possibly by maintaining cells in an intermediate stage of differentiation...