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Conditional Deletion of MSX Homeobox Genes in the Uterus Inhibits Blastocyst Implantation by Altering Uterine Receptivity

Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Developmental Cell (Impact Factor: 10.37). 11/2011; 21(6):1014-25. DOI: 10.1016/j.devcel.2011.09.010
Source: PubMed

ABSTRACT An effective bidirectional communication between an implantation-competent blastocyst and the receptive uterus is a prerequisite for mammalian reproduction. The blastocyst will implant only when this molecular cross-talk is established. Here we show that the muscle segment homeobox gene (Msh) family members Msx1 and Msx2, which are two highly conserved genes critical for epithelial-mesenchymal interactions during development, also play crucial roles in embryo implantation. Loss of Msx1/Msx2 expression correlates with altered uterine luminal epithelial cell polarity and affects E-cadherin/β-catenin complex formation through the control of Wnt5a expression. Application of Wnt5a in vitro compromised blastocyst invasion and trophoblast outgrowth on cultured uterine epithelial cells. The finding that Msx1/Msx2 genes are critical for conferring uterine receptivity and readiness to implantation could have clinical significance, because compromised uterine receptivity is a major cause of pregnancy failure in IVF programs.

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Available from: Jeeyeon Cha, Mar 15, 2014
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    • "When a blastocyst is faced with multiple luminal folds, the extra luminal folds exists as many “pitfalls” once a blastocyst falls into one fold by chance, it will establish an embryonic axis that depends on the direction of the crypt that it accommodates with, and an initial misorientation (with regard to the uterine A-AM axis) will then lead to a catastrophically disoriented uterine-embryonic axis. A recent study of uterine Msx1 deletion also reported defects in luminal closure that were characterized by the presence of extra uterine crypts for blastocyst attachment; the authors also reported increased pregnancy loss during mid-gestation48. Our current findings strongly suggest that normal establishment of embryonic-uterine orientation in mammals is not only guided by intrinsically programmed embryonic signals, but also depends on the coordinated transformation of uterine lumen as a proper guide. "
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    ABSTRACT: Coordinated uterine-embryonic axis formation and decidual remodeling are hallmarks of mammalian post-implantation embryo development. Embryonic-uterine orientation is determined at initial implantation and synchronized with decidual development. However, the molecular mechanisms controlling these events remain elusive despite its discovery a long time ago. In the present study, we found that uterine-specific deletion of Rbpj, the nuclear transducer of Notch signaling, resulted in abnormal embryonic-uterine orientation and decidual patterning at post-implantation stages, leading to substantial embryo loss. We further revealed that prior to embryo attachment, Rbpj confers on-time uterine lumen shape transformation via physically interacting with uterine estrogen receptor (ERα) in a Notch pathway-independent manner, which is essential for the initial establishment of embryo orientation in alignment with uterine axis. While at post-implantation stages, Rbpj directly regulates the expression of uterine matrix metalloproteinase in a Notch pathway-dependent manner, which is required for normal post-implantation decidual remodeling. These results demonstrate that uterine Rbpj is essential for normal embryo development via instructing the initial embryonic-uterine orientation and ensuring normal decidual patterning in a stage-specific manner. Our data also substantiate the concept that normal mammalian embryonic-uterine orientation requires proper guidance from developmentally controlled uterine signaling.Cell Research advance online publication 27 June 2014; doi:10.1038/cr.2014.82.
    Cell Research 06/2014; DOI:10.1038/cr.2014.82 · 11.98 Impact Factor
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    • "Failure of decidualization induction after removal of the luminal epithelium indicates that the epithelium acts as an obligatory transducer of decidual induction [4]. To date, several factors essential for implantation and decidualization have been identified using transgene mouse models [5] [6] [7] [8] [9] [10] [11]. However, molecular mechanisms and signaling networks critical for uterine receptivity achievement are still poorly understood. "
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    ABSTRACT: Luminal closure and embryo apposition are essential for blastocyst attachment during early pregnancy. In our preliminary microarray results (unpublished data), sodium-potassium adenosine triphosphatase (Na/K-ATPase) b1 (Atp1b1) was highly expressed in mouse uterus on Days 3 and 4 of pregnancy. However, expression and regulation of Atp1b1 in the mammalian uterus during early pregnancy are unknown. Using in situ hybridization, a strong level of Atp1b1 mRNA was detected in luminal epithelial cells on Days 3 and 4 of pregnancy (Day 1 ¼ day of vaginal plug). The expression pattern of FXYD domain-containing ion transport regulator 4 (Fxyd4) was similar to that of Atp1b1. Real-time reverse transcription polymerase chain reaction confirmed the high expression level of Atp1b1 mRNA. Compared with Day 1, the mRNA level of Atp1b1 on Days 3 and 4 increased by 3.5 AE 0.5 and 4.5 AE 0.5 fold, respectively. When the embryo invaded through epithelial cells into the maternal stromal compartment on day 5, Atp1b1 expression decreased to a basal level. Progesterone stimulated Atp1b1 expression by 2.8 AE 1 fold compared with oil in ovariectomized mice at 24 hours after treatment. Expression of Atp1b1 was further upregulated to 4 AE 0.4 fold by estrogen and progesterone. Based on time-course study, progesterone rapidly induced Atp1b1 expression at 6 and 12 hours (13.7 AE 0.5 and 16.6 AE 1.4, respectively); furthermore, this upregulation was blocked by RU486 (progesterone receptor antagonist). Transcription activity of the Atp1b1 promoter was (Day 1 ¼ day of vaginal plug) stimulated by CCAAT/enhancer binding protein beta (Cebpb). In conclusion, Atp1b1 was highly expressed in luminal epithelium during peri-implantation and upre-gulated by progesterone.
    Theriogenology 02/2013; · 1.85 Impact Factor
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    • "Coordinate proliferation and differentiation of endometrial, stromal, and epithelial cells Huet-Hudson et al. (1989), Lydon et al. (1995) Progesterone Adhesion molecules MUC1 Facilitate blastocyst capture and attachment; promote interaction between the epithelium and trophectoderm Stewart et al. (1992), Meseguer et al. (2001), Horne et al. (2005) L-selectin cadherins integrins Cytokines LIF Regulate functions of endometrial cells and embryo–maternal interactions during attachment and decidualization Stewart et al., (1992), Salamonsen et al., (2009), Menkhorst et al. (2011) IL6 IL11 Growth factors HB-EGF Locally mediate the hormone's effects on uterine cell proliferation and differentiation Paria et al., (2001a), Chen et al. (2005), Kurita et al. (2005), Zhu and Pollard (2007) IGF TGFb Homeobox gene HOXA10 Determine the early reproductive tract development and regulate post-implantation uterine development Wang and Dey (2006), Lim and Wang (2010), Daikoku et al. (2011), Nallasamy et al. (2012) "
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    ABSTRACT: Uterine receptivity is defined as a limited time period during which the uterus enters into an appropriately differentiated state that is ready for the initiation of implantation by competent blastocysts. Although various cellular aspects and molecular pathways involved in uterine receptivity have been identified by gene expression studies and genetically engineered mouse models, a comprehensive understanding of the window of uterine receptivity is still missing. This review focuses on the recent progress in this area, with particular focus on the molecular basis of stroma-epithelia dialogue and cross-talk between the blastocyst and the uterus during implantation. A better understanding of underlying mechanisms governing the window of uterine receptivity is hoped to generate new strategies to correct implantation failure and to improve pregnancy rates in women. Mol. Reprod. Dev. © 2012 Wiley Periodicals, Inc.
    Molecular Reproduction and Development 01/2013; 80(1). DOI:10.1002/mrd.22118 · 2.68 Impact Factor
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