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Loss ofPRICKLE1promotes abnormal endometrial epithelial architecture, reduced fertility, and decreased embryo implantation in mice.

ABSTRACT: Successful embryo implantation requires coordinated changes in the uterine luminal epithelium, including structural alterations, apical-basal polarity shifts, intrauterine fluid resorption, and cellular communication. These processes, collectively termed plasma membrane transformation (PMT), are crucial but poorly understood, especially regarding their regulation by planar cell polarity (PCP) proteins. PCP proteins, essential for cell organization, are understudied in the context of uterine physiology. Prickle proteins, particularly Prickle1, play critical roles in cellular polarization and tissue morphogenesis. However, their function in the endometrial epithelium during embryo implantation is unknown. To investigate Prickle1's role in uterine physiology, we developed an endometrial epithelial conditional knockout (cKO) of Prickle1 using Lactoferrin-icre. PRICKLE1 ablation in the endometrial epithelium resulted in decreased fertility and embryo implantation by gestational day 4.5. Three-dimensional imaging revealed abnormal luminal folding, impaired luminal closure, and altered glandular structure in mutant uteri. Additionally, we observed decreased aquaporin-2 expression, disrupted cellular architecture, and protein expression and localization in mutant uteri. Evidence of epithelial-to-mesenchymal transition (EMT) was found within luminal epithelial cells, further linking PRICKLE1 loss to uterine pathologies. Furthermore, altered cellular division planes and increased multinucleated cells suggested a connection to EMT. Our findings highlight PRICKLE1's critical role in the PCP pathway within the uterus, revealing its importance in the molecular and cellular responses essential for successful pregnancy establishment.

ORGANISM(S): Mus musculus

PROVIDER: GSE272552 | GEO | 2025/02/12

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) .

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, β-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.

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Loss ofPRICKLE1promotes abnormal endometrial epithelial architecture, reduced fertility, and decreased embryo implantation in mice.

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