Phospholipid flippase ATP11A brokers uterine epithelial integrity and function

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.