SpringerLink
Log in

The Notch Family Transcription Factor, RBPJκ, Modulates Glucose Transporter and Ovarian Steroid Hormone Receptor Expression During Decidualization

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

During decidualization, endometrial stromal cells differentiate into a secretory phenotype to modulate the uterine microenvironment and promote embryo implantation. This highly metabolic process relies on ovarian steroid receptors and glucose transporters. Canonical Notch signaling is mediated by the transcription factor Recombination Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). Loss of RBPJ in the mouse uterus (Pgrcre/+Rbpjflox/flox; Rbpj c-KO) results in subfertility in part due to an abnormal uterine—embryonic axis during implantation and, as described herein, decidualization failure. Induced in vivo decidualization in Rbpj c-KO mice was impaired with the downregulation of decidual markers and decreased progesterone receptor (Pgr) signaling. Consistent with in vivo mouse data, RBPJ knockdown during in vitro Human uterine fibroblast (HuF) cell decidualization results in the reduced expression of decidual marker genes along with PGR. Expression of the glucose transporter, SLC2A1, was decreased in the RBPJ-silenced HuF cells, which corresponded to decreased Slc2a1 in the secondary decidual zone of Rbpj c-KO mouse uteri. Exogenous administration of pyruvate, which bypasses the need for glucose, rescues PRL expression in RBPJ -deficient HuF cells. In summary, Notch signaling through RBPJ controls both ovarian steroid receptor PGR and glucose transporter SLC2A1 expression during decidualization, and this dysregulation likely contributes to embryo implantation failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fazleabas AT, Donnelly KM, Srinivasan S, Fortman JD, Miller JB. Modulation of the baboon (Papio anubis) uterine endometrium by chorionic gonadotrophin during the period of uterine receptivity. Proc Natl Acad Sci U S A. 1999;96(5):2543–2548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fazleabas AT, Kim JJ, Strakova Z. Implantation: embryonic signals and the modulation of the uterine environment—a review. Placenta. 2004; 25(suppl A):S26–S31.

    Article  CAS  PubMed  Google Scholar 

  3. Banerjee P, Fazleabas AT. Endometrial responses to embryonic signals in the primate. Int J Dev Biol. 2010;54(2–3):295–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Finn CA. The biology of decidual cells. Adv Reprod Physiol. 1971;5:1–26.

    CAS  PubMed  Google Scholar 

  5. Jayatilak PG, Glaser LA, Warshaw ML, Herz Z, Gruber JR, Gibori G. Relationship between luteinizing hormone and decidual luteotropin in the maintenance of luteal steroidogenesis. Biol Reprod. 1984;31(3):556–564.

    Article  CAS  PubMed  Google Scholar 

  6. Lala PK, Graham CH. Mechanisms of trophoblast invasiveness and their control: the role of proteases and protease inhibitors. Cancer Metastasis Rev. 1990;9(4):369–379.

    Article  CAS  PubMed  Google Scholar 

  7. Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. 2014;35(6):851–905.

    Article  CAS  PubMed  Google Scholar 

  8. Weimar CH, Macklon NS, Post Uiterweer ED, Brosens JJ, Gellersen B. The motile and invasive capacity of human endometrial stromal cells: implications for normal and impaired reproductive function. Hum Reprod Update. 2013;19(5):542–557.

    Article  CAS  PubMed  Google Scholar 

  9. Anacker J, Segerer SE, Hagemann C, et al. Human decidua and invasive trophoblasts are rich sources of nearly all human matrix metalloproteinases. Mol Hum Reprod. 2011;17(10):637–652.

    Article  CAS  PubMed  Google Scholar 

  10. Grewal S, Carver J, Ridley AJ, Mardon HJ. Human endometrial stromal cell rho GTPases have opposing roles in regulating focal adhesion turnover and embryo invasion in vitro. Biol Reprod. 2010;83(1):75–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Plaks V, Rinkenberger J, Dai J, et al. Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction. Proc Natl Acad Sci U S A. 2013;110(27):11109–11114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Salker M, Teklenburg G, Molokhia M, et al. Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss. PLoS One. 2010;5(4):e10287.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18(12):1754–1767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284(5415):770–776.

    Article  CAS  PubMed  Google Scholar 

  15. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678–689.

    Article  CAS  PubMed  Google Scholar 

  16. D’Souza B, Meloty-Kapella L, Weinmaster G. Canonical and non-canonical Notch ligands. Curr Top Dev Biol. 2010;92:73–129.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol. 2003;194(3):237–255.

    Article  CAS  PubMed  Google Scholar 

  19. Tamura K, Taniguchi Y, Minoguchi S, et al. Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Curr Biol. 1995;5(12):1416–1423.

    Article  CAS  PubMed  Google Scholar 

  20. Kageyama R, Ohtsuka T. The Notch-Hes pathway in mammalian neural development. Cell Res. 1999;9(3):179–188.

    Article  CAS  PubMed  Google Scholar 

  21. Kim JJ, Jaffe RC, Fazleabas AT. Insulin-like growth factor binding protein-1 expression in baboon endometrial stromal cells: regulation by filamentous actin and requirement for de novo protein synthesis. Endocrinology. 1999;140(2):997–1004.

    Article  CAS  PubMed  Google Scholar 

  22. Jasinska A, Strakova Z, Szmidt M, Fazleabas AT. Human chorionic gonadotropin and decidualization in vitro inhibits cytochalasin-D-induced apoptosis in cultured endometrial stromal fibroblasts. Endocrinology. 2006;147(9):4112–4121.

    Article  CAS  PubMed  Google Scholar 

  23. Afshar Y, Miele L, Fazleabas AT. Notch1 is regulated by chorionic gonadotropin and progesterone in endometrial stromal cells and modulates decidualization in primates. Endocrinology. 2012;153(6):2884–2896.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Strug MR, Su R, Young JE, et al. Intrauterine human chorionic gonadotropin infusion in oocyte donors promotes endometrial synchrony and induction of early decidual markers for stromal survival: a randomized clinical trial. Hum Reprod. 2016;31(7):1552–1561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Afshar Y, Jeong JW, Roqueiro D, et al. Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB J. 2012;26(1):282–294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Su RW, Strug MR, Joshi NR, et al. Decreased Notch pathway signaling in the endometrium of women with endometriosis impairs decidualization. J Clin Endocrinol Metab. 2015;100(3):E433–E442.

    Article  CAS  PubMed  Google Scholar 

  27. Otti GR, Saleh L, Velicky P, Fiala C, Pollheimer J, Knofler M. Notch2 controls prolactin and insulin-like growth factor binding protein-1 expression in decidualizing human stromal cells of early pregnancy. PLoS One. 2014;9(11):e112723.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Zhang S, Kong S, Wang B, et al. Uterine Rbpj is required for embryonic-uterine orientation and decidual remodeling via Notch pathway-independent and -dependent mechanisms. Cell Res. 2014;24(8):925–942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Strug MR, Su RW, Kim TH, et al. RBPJ mediates uterine repair in the mouse and is reduced in women with recurrent pregnancy loss. FASEB J. 2018;32(5):2452–2466. fj201701032 R.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Frolova AI, Moley KH. Glucose transporters in the uterus: an analysis of tissue distribution and proposed physiological roles. Reproduction. 2011;142(2):211–220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. von Wolff M, Ursel S, Hahn U, Steldinger R, Strowitzki T. Glucose transporter proteins (GLUT) in human endometrium: expression, regulation, and function throughout the menstrual cycle and in early pregnancy. J Clin Endocrinol Metab. 2003;88(8):3885–3892.

    Article  CAS  Google Scholar 

  32. Frolova A, Flessner L, Chi M, Kim ST, Foyouzi-Yousefi N, Moley KH. Facilitative glucose transporter type 1 is differentially regulated by progesterone and estrogen in murine and human endometrial stromal cells. Endocrinology. 2009;150(3):1512–1520.

    Article  CAS  PubMed  Google Scholar 

  33. Kim ST, Moley KH. Regulation of facilitative glucose transporters and AKT/MAPK/PRKAA signaling via estradiol and progesterone in the mouse uterine epithelium. Biol Reprod. 2009;81(1):188–198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Frolova AI, Moley KH. Quantitative analysis of glucose transporter mRNAs in endometrial stromal cells reveals critical role of GLUT1 in uterine receptivity. Endocrinology. 2011;152(5):2123–2128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Augustin R. The protein family of glucose transport facilitators: it’s not only about glucose after all. IUBMB Life. 2010;62(5):315–333.

    CAS  PubMed  Google Scholar 

  36. Yamaguchi M, Sakata M, Ogura K, Miyake A. Gestational changes of glucose transporter gene expression in the mouse placenta and decidua. J Endocrinol Invest. 1996;19(8):567–569.

    Article  CAS  PubMed  Google Scholar 

  37. Maekawa Y, Ishifune C, Tsukumo S, Hozumi K, Yagita H, Yasutomo K. Notch controls the survival of memory CD4+ T cells by regulating glucose uptake. Nat Med. 2015;21(1):55–61.

    Article  CAS  PubMed  Google Scholar 

  38. Oka C, Nakano T, Wakeham A, et al. Disruption of the mouse RBP-J kappa gene results in early embryonic death. Development. 1995;121(10):3291–3301.

    Article  CAS  PubMed  Google Scholar 

  39. Han H, Tanigaki K, Yamamoto N, et al. Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. International immunology. 2002;14(6):637–645.

    Article  CAS  PubMed  Google Scholar 

  40. Lee K, Jeong J, Kwak I, et al. Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nat Genet. 2006;38(10):1204–1209.

    Article  CAS  PubMed  Google Scholar 

  41. Soyal SM, Mukherjee A, Lee KY, et al. Cre-mediated recombination in cell lineages that express the progesterone receptor. Genesis. 2005;41(2):58–66.

    Article  CAS  PubMed  Google Scholar 

  42. Fuhrich DG, Lessey BA, Savaris RF. Comparison of HSCORE assessment of endometrial beta3 integrin subunit expression with digital HSCORE using computerized image analysis (ImageJ). Anal Quant Cytopathol Histpathol. 2013;35(4):210–216.

    PubMed  PubMed Central  Google Scholar 

  43. Kim JJ, Jaffe RC, Fazleabas AT. Comparative studies on the in vitro decidualization process in the baboon (Papio anubis) and human. Biol Reprod. 1998;59(1):160–168.

    Article  CAS  PubMed  Google Scholar 

  44. Strakova Z, Srisuparp S, Fazleabas AT. Interleukin-1beta induces the expression of insulin-like growth factor binding protein-1 during decidualization in the primate. Endocrinology. 2000;141(12):4664–4670.

    Article  CAS  PubMed  Google Scholar 

  45. Large MJ, DeMayo FJ. The regulation of embryo implantation and endometrial decidualization by progesterone receptor signaling. Mol Cell Endocrinol. 2012;358(2):155–165.

    Article  CAS  PubMed  Google Scholar 

  46. Rahman MA, Li M, Li P, Wang H, Dey SK, Das SK. Hoxa-10 deficiency alters region-specific gene expression and perturbs differentiation of natural killer cells during decidualization. Dev Biol. 2006;290(1):105–117.

    Article  CAS  PubMed  Google Scholar 

  47. Korgun ET, Demir R, Hammer A, et al. Glucose transporter expression in rat embryo and uterus during decidualization, implantation, and early postimplantation. Biol Reprod. 2001;65(5):1364–1370.

    Article  CAS  PubMed  Google Scholar 

  48. Su RW, Strug MR, Jeong JW, Miele L, Fazleabas AT. Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility. Proc Natl Acad Sci U S A. 2016;113(8):2300–2305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tan J, Raja S, Davis MK, Tawfik O, Dey SK, Das SK. Evidence for coordinated interaction of cyclin D3 with p21 and cdk6 in directing the development of uterine stromal cell decidualization and polyploidy during implantation. Mech Dev. 2002;111(1–2):99–113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kulic I, Robertson G, Chang L, et al. Loss of the Notch effector RBPJ promotes tumorigenesis. J Exp Med. 2015;212(1):37–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Conaghan J, Handyside AH, Winston RM, Leese HJ. Effects of pyruvate and glucose on the development of human preimplantation embryos in vitro. J Reprod Fertil. 1993;99(1):87–95.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, 400 Monroe Avenue NW, GRRC, Room 3020, Grand Rapids, MI, 49503, USA

    Michael R. Strug DO, PhD, Ren-Wei Su PhD, Tae Hoon Kim PhD, Jae-Wook Jeong PhD & Asgerally Fazleabas PhD

  2. Department of Obstetrics and Gynecology, Spectrum Health, Grand Rapids, MI, USA

    Michael R. Strug DO, PhD

Authors
  1. Michael R. Strug DO, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ren-Wei Su PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tae Hoon Kim PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jae-Wook Jeong PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Asgerally Fazleabas PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Asgerally Fazleabas PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Strug, M.R., Su, RW., Kim, T.H. et al. The Notch Family Transcription Factor, RBPJκ, Modulates Glucose Transporter and Ovarian Steroid Hormone Receptor Expression During Decidualization. Reprod. Sci. 26, 774–784 (2019). https://doi.org/10.1177/1933719118799209

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719118799209

Keywords

Search

Navigation