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Foxa2-dependent uterine glandular cell differentiation is essential for successful implantation

ABSTRACT: Uterine receptivity (the window of implantation) is essential for successful implantation. The concept of uterine receptivity was first discovered 50 years ago by Psychoyos. In mice, uterine receptivity begins with the secretion of LIF from uterine glands stimulated by estrogen on the morning of day 4 pregnancies. However, some implantation failure is due to the lack of responses to the estrogen secretion. The current study reveals that uterine glands undergo a differentiation process with increases in more branches during the preimplantation period. The single cell RNA profiling of glandular cells identifies that LIF is expressed exclusively in a Prss29+ subgroup of glands in response to estrogen secretion on day 4 of pregnancy. Previous studies have shown that Foxa2 deficiency in uterine glands results in implantation failure due to lack of LIF production. Interestingly, Foxa2-deficient glands fail to develop branches and the functional Prss29+ subgroup of gland cells, indicating FOXA2 is obligatory for normal glandular differentiation prior to implantation. We found that this group develops by the evening of day 3 of pregnancy prior to estrogen secretion on day 4 mornings. We noticed that Lif mRNA signals are detected in the uterus comprising the Prss29+ subgroup. Our findings indicate that uterine glands undergo a FOXA2-dependent maturation process to acquire the competence, which we have termed the “transitional phase,” necessary to respond to estrogen. This newly identified glandular "transitional phase" represents a landmark concept in the study of uterine receptivity and implantation biology.

ORGANISM(S): Mus musculus

PROVIDER: GSE275806 | GEO | 2025/02/15

REPOSITORIES: GEO

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Project description:Embryo implantation into a receptive endometrium is tightly regulated by a variety of maternal factors, including cytokines, growth factors and transcription factors. Previous studies identified the leukaemia inhibitory factor (LIF), produced in uterine glands, as an essential factor for implantation. It was shown that LIF acts via its cell surface receptor to activate the transcription factor STAT3 in the uterine epithelial cells. However, the mechanisms via which STAT3 promotes uterine receptivity remain unknown. To address the molecular pathways regulated by STAT3 in the uterus, we created mice in which Stat3 gene is conditionally inactivated in uterine epithelium. These mutant mice are infertile due to implantation failure and exhibit a lack of embryo attachment to the luminal epithelium. Gene expression profiling of the epithelial tissue impaired in STAT3 activation revealed dysregulated expression of specific components of junctional complexes, including E-cadherin, M-NM-2-catenin, and claudins, which critically regulate epithelial cell polarity and embryo attachment. Additionally, mice lacking functional epithelial STAT3 showed markedly reduced stromal proliferation and differentiation, indicating that this transcription factor controls stromal function via a paracrine mechanism. The stromal defect arose from a drastic reduction in the production of several members of the epidermal growth factor (EGF) family in luminal epithelium of mutant uteri and consequent lack of activation of EGF receptor signaling and mitotic activity in the stromal cells. Collectively, our results uncovered intricate signaling networks operating downstream of STAT3 in uterine epithelium that regulate epithelial cell polarity, and stromal proliferation and differentiation, which are critical determinants of successful implantation. To identify the downstream targets of STAT3 in mouse uterine epithelial cells during pregnancy, we performed gene expression profling of mouse uterine epithelial cells on day 4 of pregnancy between Stat3 flox control and SW d/d mice. This led to the identification of several junctional molecules (Claudins and Catenins) that are negatively regulated by STAT3 at the time of implantation. Mouse uteirne epithelial cells were isolated from control and knockout mice on the morning of day 4 of pregnancy. (n=3 for each sample), pooled total RNA from these cells was then hybridized to high density affymetrix microarrays according to the Affymetrix protocol (Mouse Genome 430A 2.0 Array) .

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Foxa2-dependent uterine glandular cell differentiation is essential for successful implantation

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