YAP1 and WWTR1 are required for murine pregnancy initiation

Endometrial stromal cell decidualization is required for pregnancy success. Although this process is integral to fertility, many of the intricate molecular mechanisms contributing to decidualization remain undefined. One pathway that has been implicated in endometrial stromal cell decidualization in humans in vitro, is the Hippo signaling pathway. Two previously conducted studies showed that the effectors of the Hippo signaling pathway, YAP1 and WWTR1, were required for decidualization of primary stromal cells in culture. To investigate the in vivo role of YAP1 and WWTR1 in decidualization and pregnancy initiation, we generated a Progesterone Cre mediated partial double knockout (pdKO) of Yap1 and Wwtr1. Female pdKOs exhibited subfertility, a compromised decidualization response, partial interruption in embryo transport, blunted endometrial receptivity, delayed implantation and subsequent embryonic development, and a unique transcriptional profile. Bulk mRNA sequencing revealed aberrant maternal remodeling evidenced by significant alterations in extracellular matrix proteins at 7.5 days post coitus in pdKO dams, and enrichment for terms associated with fertility compromising diseases like pre-eclampsia and endometriosis. Our results indicate a required role for YAP1 and WWTR1 for successful mammalian uterine function and pregnancy success. To investigate the role of Yap1 and Wwtr1 in the murine female reproductive tract, we generated Progesterone Cre mediated knockout of one allele of Yap and two alleles of Wwtr1 (Pgr Cre/+ Yap +/f Wwtr1 f/f). Pregnant female uterine cross sections from floxed controls (Pgr +/+ Yap f/f Wwtr1 f/f) (n=4) and knockouts (Pgr Cre/+ Yap +/f Wwtr1 f/f) (n=3) at 7.5 days post coitus were sent for bulk mRNA sequencing to determine the transcriptional consequences of Yap and Wwtr1 loss in the murine uterus during pregnancy.