In brief: The HIPPO signaling effectors YAP1 and WWTR1 are required for murine pregnancy initiation, and mutation of these factors compromises the decidualization response and overall pregnancy success.
Abstract: 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 are required for decidualization of primary endometrial stromal cells in vitro. To investigate the in vivo role of YAP1 and WWTR1 in decidualization and pregnancy initiation, we generated progesterone receptor Cre-mediated mutation of a combination of Yap1 and Wwtr1 alleles. Female Yap1 and Wwtr1 triple allele mutants exhibited subfertility, a compromised decidualization response, decreased endometrial receptivity, delayed embryonic development and a unique transcriptional profile at 7.5 days post-coitus (dpc). Bulk mRNA sequencing revealed aberrant maternal remodeling evidenced by significant alterations in extracellular matrix-encoding genes at 7.5 dpc in mutant dams and enrichment for terms associated with fertility-compromising diseases such as pre-eclampsia and endometriosis. In addition, differentially expressed genes overlapped directionally with estrogen receptor- and epidermal growth factor receptor-regulated genes as identified by microarray. Our results indicate that Yap1 and Wwtr1 are necessary for successful mammalian pregnancy initiation.