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Phospholipid flippase ATP11A brokers uterine epithelial integrity and function

ABSTRACT: Uterine adaptations driven by the steroid hormones estrogen and progesterone are pivotal for embryo implantation and, ultimately for a successful pregnancy. Here, we show that genetic ablation of the membrane lipid flippase Atp11a in mice causes severe deficits in this hormonal response and profound defects in the morphological organization and transcriptional profile of the uterine epithelial compartment where ATP11A is expressed. Atp11a-null uterine epithelial cells lack tight junctions, and the luminal epithelium exhibits profound disruptions to cellular morphology as it displays a loss of the columnar epithelial architecture and instead acquires a multi-layered morphology of rounded cells resembling a squamous epithelium. Furthermore, the specification of luminal epithelial cells remains incomplete as they maintain expression of the normally gland-restricted marker FOXA2. The uterine glands of Atp11a-null females are depleted for progenitor cells marked by SOX9, PAX8, LGR5 and PROM1. Collectively, these defects likely underpin the frequent early pregnancy losses in Atp11a-depleted females. Most intriguingly, however, loss of only a single functional Atp11a allele causes a higher frequency of abnormal placental trophoblast differentiation as well as a higher incidence of congenital heart defects in wild-type embryos. These data highlight the far-reaching impact of uterine dysfunction on reproductive outcome and highlight the importance of the maternal genotype in the etiology of developmental disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE278900 | GEO | 2025/04/07

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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Phospholipid flippase ATP11A brokers uterine epithelial integrity and function

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