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 in mice that genetic ablation of the membrane lipid flippase <i>Atp11a</i> causes severe deficits in this hormonal response and profound defects in the morphological organization and transcriptional profile of the uterine epithelial compartment where <i>Atp11a</i> is expressed. <i>Atp11a</i>-null uterine epithelial cells lack tight junctions, and the luminal epithelium exhibits profound disruptions to cellular morphology. Interestingly, the specification of luminal epithelial cells remains incomplete as they maintain expression of the normally gland-restricted marker FOXA2. The uterine glands of <i>Atp11a</i>-null females are depleted for progenitor cells marked by SOX9, PAX8, LGR5, and PROM1. Collectively, these findings point to a uterine receptivity deficit that underpins the frequent failure of <i>Atp11a</i>-depleted females to establish a successful pregnancy. Most intriguingly, however, loss of only a single functional <i>Atp11a</i> allele causes a higher frequency of abnormal placental trophoblast differentiation as well as a higher incidence of developmental heart defects in wild-type embryos. These data emphasize the far-reaching impact of uterine dysfunction on reproductive outcome and highlight the importance of the maternal genotype in the etiology of developmental disorders.