Human reproduction is complex and fairly inefficient. More than 30% of conceptions result in spontaneous abortion with most losses occurring around the time of implantation. These unwanted pregnancy losses contribute to major psychological, economical, and clinical conflicts. Inadequate uterine milieu is one cause for this failure?to explore deeper into the mechanics of successful pregnancy, we recognize that effective two-way interactions between a competent blastocyst and the receptive uterus are a prerequisite for implantation in placental mammals including humans. The blastocyst will implant only when this molecular dialogue is established. Normally, implantation in mice occurs within a specialized implantation chamber (crypt) formed by luminal epithelial (LE) evaginations towards the antimesometrial (AM) side of the uterus. The underlying mechanism by which evenly spaced crypts are formed towards the AM pole remains elusive. Our recent work in mice shows that regulated Wnt5a-ROR signaling is critical to implantation and pregnancy establishment. We propose that this signaling is mediated by planar cell polarity (PCP) by engaging PCP components Vangl2, Scribble, Celsr1 and Dvl2. We will test the hypothesis that PCP activity in collaboration with non-canonical Wnt5a-ROR signaling directs crypt formation and implantation.
Aim 1 will test if major PCP signaling constituents are active in the uterus around the time of implantation.
Aim 2 will investigate whether uterine PCP activity is critical for crypt formation for implantation through the use of genetic mouse models. Our preliminary results in mice with uterine deletion of Vangl2 (a core component in PCP signaling) show defective implantation and compromised pregnancy outcomes. These results have created a unique window of opportunity to generate molecular and genetic information on a potential mechanism by which the uterine environment becomes conducive to blastocyst homing in the crypt for implantation and pregnancy establishment. The genetic mouse models provide mechanistic information relevant to female fertility which is not feasible to perform in humans. There is a strong possibility that PCP signaling plays a major role in human implantation, since the human proteome atlas has documented the expression of Vangl2, Vangl1 and Wnt5a in the human uterus. Thus, it is prudent to gather mechanistic and genetic evidence regarding PCP?s requirement in implantation in mouse models to better understand human implantation.

Public Health Relevance

The underlying mechanism by which implantation chambers (crypt) are formed for blastocyst homing and implantation is not clearly understood. The proposed study will explore the role of planar cell polarity (PCP) signaling directing crypt formation for implantation. The results will help to better understand implantation biology and develop novel strategies to improve pregnancy rates in women with poor fertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD068524-09
Application #
9739086
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Cheng, Clara M
Project Start
2011-09-26
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Hsu, Alice H; Lum, Michelle A; Shim, Kang-Sup et al. (2018) Crosstalk between PKC? and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium. Cell Rep 24:655-669
Liang, Xiaohuan; Daikoku, Takiko; Terakawa, Jumpei et al. (2018) The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten. PLoS Genet 14:e1007630
Sun, Xiaofei; Tavenier, Alexandra; Deng, Wenbo et al. (2018) Metformin attenuates susceptibility to inflammation-induced preterm birth in mice with higher endocannabinoid levels. Biol Reprod 98:208-217
Yuan, Jia; Deng, Wenbo; Cha, Jeeyeon et al. (2018) Tridimensional visualization reveals direct communication between the embryo and glands critical for implantation. Nat Commun 9:603
Cha, Jeeyeon; Dey, Sudhansu K (2017) Hunting for Fox(A2): Dual roles in female fertility. Proc Natl Acad Sci U S A 114:1226-1228
Sun, Xiaofei; Ito, Junya; Potter, Sarah J et al. (2017) Extragonadal oocytes residing in the mouse ovarian hilum contribute to fertility. Biol Reprod 96:1060-1070
Lanekoff, Ingela; Cha, Jeeyeon; Kyle, Jennifer E et al. (2016) Trp53 deficient mice predisposed to preterm birth display region-specific lipid alterations at the embryo implantation site. Sci Rep 6:33023
Sones, Jenny L; Cha, Jeeyeon; Woods, Ashley K et al. (2016) Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model. JCI Insight 1:
Yuan, Jia; Cha, Jeeyeon; Deng, Wenbo et al. (2016) Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation. Proc Natl Acad Sci U S A 113:E8079-E8088
Sun, Xiaofei; Park, Craig B; Deng, Wenbo et al. (2016) Uterine inactivation of muscle segment homeobox (Msx) genes alters epithelial cell junction proteins during embryo implantation. FASEB J 30:1425-35

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