Phospholipid flippase ATP11A brokers uterine epithelial integrity and function
成果类型：
Article
署名作者：
Krala, Alexa; Tsolova, Aleksandra O.; Radford, Bethany N.; Jadli, Anshul S.; Zhao, Xiang; Blackwell, Danielle; Narang, Ankita; Dean, Wendy; Hemberger, Myriam
署名单位：
University of Calgary; University of Calgary; University of Calgary
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-11487
DOI：
10.1073/pnas.2420617122
发表日期：
2025-04-29
关键词：
embryo implantation
gland development
human endometrium
long-term
mouse
adhesion
foxa2
expression
binding
摘要：
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 Atp11a 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. Interestingly, 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 findings point to a uterine receptivity deficit that underpins the frequent failure of Atp11a-depleted females to establish a successful pregnancy. 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 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.