Human reproduction is complex and not very efficient. More than 30% of conceptions result in spontaneous abortion with most losses occurring around the time of implantation due to an inadequate uterine milieu. Unwanted pregnancy loss is a major psychological, economical and clinical problem. One prerequisite for implantation in placental mammals is an effective two-way interaction between an implantation- competent blastocyst and the receptive uterus. The blastocyst will implant only when this molecular dialogue is established. The underlying mechanism by which a uterus transits from the pre-receptive to the receptive to the non-receptive phase remains unknown. We hypothesize that two highly conserved genes (Msx1 and Msx2) of the muscle segment homeobox (Msh) family have key roles in uterine receptivity and non-receptivity to implantation. In the proposed study, we will test the hypothesis that these morphogenetic genes, critical for epithelial-mesenchymal interactions during development, also play crucial roles in implantation by altering the epithelial cell polarity and integrity via a non- canonical Wnt signaling involving E-cadherin-2-catenin complex formation. To test our hypothesis, we will pursue two specific aims in mice. The first specific aim will test the hypothesis that while Msx1 is a major critical factor in implantation, Msx2 has a compensatory role if Msx1 is missing. The second specific aim will test the hypothesis that Msx1 and/or Msx2 direct implantation by influencing the epithelial cell polarity and integrity. The overall goal of this proposal is to better understand the mechanisms that direct uterine receptivity and non-receptivity with the aim of improving female fertility. We will use conditionally gene-deleted mouse models to address the molecular basis of these events, since these models provide mechanistic information relevant to female fertility which cannot be pursued in humans due to ethical restrictions. However, we will collaborate with clinician scientists to determine clinical correlates of our findings in mice.

Public Health Relevance

The underlying mechanism by which the uterus transits from the perceptive to receptive to non-receptive phases in the context of embryo implantation is not clearly understood. The proposed study will explore the role and mechanism of Msx1 and/or Msx2, two homeotic transcription factors, in this transition. The results may help developing novel strategies to improve pregnancy rates in women with poor fertility.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HD068524-04
Application #
8691431
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Yoshinaga, Koji
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Cha, Jeeyeon; Bartos, Amanda; Park, Craig et al. (2014) Appropriate crypt formation in the uterus for embryo homing and implantation requires Wnt5a-ROR signaling. Cell Rep 8:382-92
Cha, Jeeyeon; Dey, Sudhansu K (2014) Cadence of procreation: orchestrating embryo-uterine interactions. Semin Cell Dev Biol 34:56-64
Sun, Xiaofei; Terakawa, Jumpei; Clevers, Hans et al. (2014) Ovarian LGR5 is critical for successful pregnancy. FASEB J 28:2380-9
Daikoku, Takiko; Ogawa, Yuya; Terakawa, Jumpei et al. (2014) Lactoferrin-iCre: a new mouse line to study uterine epithelial gene function. Endocrinology 155:2718-24
Romero, Roberto; Dey, Sudhansu K; Fisher, Susan J (2014) Preterm labor: one syndrome, many causes. Science 345:760-5
Sun, Xiaofei; Dey, Sudhansu K (2014) Synthetic cannabinoids and potential reproductive consequences. Life Sci 97:72-7
Raines, Anna M; Adam, Mike; Magella, Bliss et al. (2013) Recombineering-based dissection of flanking and paralogous Hox gene functions in mouse reproductive tracts. Development 140:2942-52
Sun, Xiaofei; Bartos, Amanda; Whitsett, Jeffrey A et al. (2013) Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses. Mol Endocrinol 27:1492-501
Lanekoff, Ingela; Burnum-Johnson, Kristin; Thomas, Mathew et al. (2013) High-speed tandem mass spectrometric in situ imaging by nanospray desorption electrospray ionization mass spectrometry. Anal Chem 85:9596-603
Cha, Jeeyeon; Hirota, Yasushi; Dey, Sudhansu K (2012) Sensing senescence in preterm birth. Cell Cycle 11:205-6

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