Molecular signaling in uterine receptivity to implantation

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Summary 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.