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: 9.71). 11/2011; 21(6):1014-25. DOI: 10.1016/j.devcel.2011.09.010
Source: PubMed


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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    • "These in vivo observations are supported by in vitro results that trophoblast cells engulf primary uterine epithelial cells. We have shown previously that LE cells begin to lose their apicobasal polarity pending blastocyst implantation (Cha et al., 2014; Daikoku et al., 2011). On day 5, the intrusive trophoblast cells take advantage of the less polarized loosened LE cells and adopt a cell-in-cell invasive behavior to engulf and internalize bordering LE cells to make contact with stromal cells. "
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    ABSTRACT: During implantation, uterine luminal epithelial (LE) cells first interact with the blastocyst trophectoderm. Within 30 hr after the initiation of attachment, LE cells surrounding the blastocyst in the implantation chamber (crypt) disappear, allowing trophoblast cells to make direct physical contact with the underneath stroma for successful implantation. The mechanism for the extraction of LE cells was thought to be mediated by apoptosis. Here, we show that LE cells in direct contact with the blastocyst are endocytosed by trophoblast cells by adopting the nonapoptotic cell-in-cell invasion process (entosis) in the absence of caspase 3 activation. Our in vivo observations were reinforced by the results of co-culture experiments with primary uterine epithelial cells with trophoblast stem cells or blastocysts showing internalization of epithelial cells by trophoblasts. We have identified entosis as a mechanism to remove LE cells by trophoblast cells in implantation, conferring a role for entosis in an important physiological process. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Preview · Article · Apr 2015 · Cell Reports
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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.
    Full-text · Article · Jun 2014 · Cell Research
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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.
    Full-text · Article · Feb 2013 · Theriogenology
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