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

Abstract

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.ffective reciprocal cross-talk between the receptive uterus and a competent blastocyst is critical for successful implantation (1). In nearly all mammals studied, the uterus differentiates into a receptive state timed appropriately with the migration of blastocysts into the uterus to initiate bidirectional communication for implantation. The receptive state is transient; in mice the uterus becomes receptive on day 4 of pregnancy (day 1 = vaginal plug) and refractory to implantation by the afternoon of day 5 (2). The coordinated actions of progesterone and estrogen regulate the proliferation and/or differentiation of major uterine cell types in a spatiotemporal manner to establish this brief window of receptivity for implantation. These changes involve an interplay of ovarian hormones, transcription factors, growth factors, morphogens, cytokines, and other signaling molecules. Aberrations or defects in any of these pathways may result in implantation failure or defective implantation, which propagates adverse ripple effects through the remaining course of gestation, compromising pregnancy outcomes (2-5).Blood vessels enter the uterus from the mesometrium and delineate the uterus into mesometrial (M) and antimesometrial (AM) domains. In mice, blastocyst attachment occurs within specialized crypts (implantation chambers), which originate as epithelial evaginations from the main lumen at orderly spaced intervals at the AM domain. The formation of these directed evaginations is initiated on the morning of day 3, and they elongate by the afternoon of day 4 for blastocyst attachment and subsequent crypt formation in the evening along the Wnt5a gradient (6). Blastocyst attachment coincides with increased endometrial vascular permeability at the site of the attachment, which can...

Identification of uterine pacemaker regions at the myometrial–placental interface in the rat

“…The asymmetry of implantation is encoded by a Wnt5a gradient across the uterine lumen that creates a timed evagination and subsequent implantation crypt (Cha et 2014). The regular spacing of the implantation crypts is directed by planar cell polarity signalling, as mice deficient in the non-canonical Wnt intermediary Vangl2 exhibit defective crypt formation and severely compromised pregnancy outcomes (Yuan et al 2016). Our data suggests that the asymmetry of patterning, combined with the association of bridges with vasculature, promotes co-localization of implantation with the vascular supply of the mesometrial axis, and the bridge-like structures of myometrium that provide electrical access to the entire myometrial network.…”

“…Our data suggests that the asymmetry of patterning, combined with the association of bridges with vasculature, promotes co-localization of implantation with the vascular supply of the mesometrial axis, and the bridge-like structures of myometrium that provide electrical access to the entire myometrial network. It remains unclear whether the bridge-like structures are formed postnatally concurrently with the circular and longitudinal layers (Brody & Cunha, 1989) or at the same time as the crypt structures of the lumen Cha et al 2014;Yuan et al 2016). However, as the vascular network forms before the circular and longitudinal layers (Brody & Cunha, 1989), we surmise that bridges form postnatally through the paths created by the vascular bed.…”

“…2014). The regular spacing of the implantation crypts is directed by planar cell polarity signalling, as mice deficient in the non‐canonical Wnt intermediary Vangl2 exhibit defective crypt formation and severely compromised pregnancy outcomes (Yuan et al . 2016).…”

Molecular mechanisms of embryonic implantation in mammals: Lessons from the gene manipulation of mice

“…Some studies showed that the loosening of cell‐cell junctions in the mouse uterine epithelium through a downregulation of E‐cadherin was a prerequisite for blastocyst attachment . Other recent investigations revealed that downstream factors of Wnt5a; that is, receptor tyrosine kinase‐like orphan receptor 1/2 (Ror1/2) and Vangl 1/2, were both essential and that the disruption of Wnt5a‐Ror‐Vangl signaling results in disorderly epithelial projections, crypt formation, and embryo spacing, and impaired implantation . Another recent study showed that Rbbj, the nuclear transducer of Notch signaling, conferred an on‐time uterine lumen shape transformation by physically interacting with uterine ERα in a Notch pathway‐independent manner .…”

“…64,65 Other recent investigations revealed that downstream factors of Wnt5a; that is, receptor tyrosine kinase-like orphan receptor 1/2 (Ror1/2) and Vangl 1/2, were both essential and that the disruption of Wnt5a-Ror-Vangl signaling results in disorderly epithelial projections, crypt formation, and embryo spacing, and impaired implantation. 66,67 Another recent study showed that Rbbj, the nuclear transducer of Notch signaling, conferred an on-time uterine lumen shape transformation by physically interacting with uterine ERα in a Notch pathway-independent manner. 68 It is understood that the estrogendependent signaling is required for normal mammalian embryouterus interaction via growth factors, cell-cell adhesion, and cell polarity pathways.…”