Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation

Significance Blastocyst implantation is a complex process that coordinates reciprocal embryo–uterine interactions. The uterus is demarcated by mesometrial (A)–antimesometrial (AM) domains; implantation occurs at regularly spaced intervals along the longitudinal axis of the AM pole, within specialized implantation chambers (crypts). The organized crypt formation in the rodent uterus was first observed in 1901, but the mechanism driving this phenomenon remained unknown. We found that planar cell polarity (PCP) signaling coordinates luminal epithelial evaginations toward the AM domain to form crypts for embryo homing and implantation in mice. Disruption of PCP signaling by inactivation of Vang-like protein 2, but not Vang-like protein 1, in the uterus disturbs the regular formation of epithelial evaginations and crypts, disrupting implantation and decidualization and severely compromising pregnancy outcomes. Blastocyst implantation is a complex process requiring coordination of a dynamic sequence of embryo–uterine interactions. Blood vessels enter the uterus from the mesometrium, demarcating the uterus into mesometrial (M) and antimesometrial (AM) domains. Implantation occurs along the uterine longitudinal axis within specialized implantation chambers (crypts) that originate within the evaginations directed from the primary lumen toward the AM domain. The morphological orientation of crypts in rodent uteri was recognized more than a century ago, but the mechanism remained unknown. Here we provide evidence that planar cell polarity (PCP) signaling orchestrates directed epithelial evaginations to form crypts for implantation in mice. Uterine deletion of Vang-like protein 2, but not Vang-like protein 1, conferred aberrant PCP signaling, misdirected epithelial evaginations, defective crypt formation, and blastocyst attachment, leading to severely compromised pregnancy outcomes. The study reveals a previously unrecognized role for PCP in executing spatial cues for crypt formation and implantation. Because PCP is an evolutionarily conserved phenomenon, our study is likely to inspire implantation studies of this signaling pathway in humans and other species.

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