Moldovan Genna E, Massri Noura, Vegter Erin L, Pauneto-Delgado Ivonne N, Burns Gregory W, Joshi Niraj, Gu Bin, Arora Ripla, Fazleabas Asgerally T
Reproduction. 2025 Jan 2;169(1). doi: 10.1530/REP-24-0355. Print 2025 Jan 1.
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.
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.
HIPPO信号通路效应因子YAP1和WWTR1是小鼠妊娠起始所必需的，这些因子的突变会损害蜕膜化反应和整体妊娠成功率。
子宫内膜基质细胞蜕膜化是妊娠成功所必需的。尽管这一过程对生育至关重要，但许多促成蜕膜化的复杂分子机制仍不明确。在体外，HIPPO信号通路是与人类子宫内膜基质细胞蜕膜化有关的一条途径。之前的两项研究表明，HIPPO信号通路效应因子YAP1和WWTR1是体外原代子宫内膜基质细胞蜕膜化所必需的。为了研究YAP1和WWTR1在蜕膜化和妊娠起始中的体内作用，我们通过孕酮受体Cre介导产生了Yap1和Wwtr1等位基因组合的突变。雌性Yap1和Wwtr1三等位基因突变体表现出生育力低下、蜕膜化反应受损、子宫内膜容受性降低、胚胎发育延迟以及在交配后7.5天（dpc）有独特的转录谱。大量mRNA测序显示，突变母鼠在7.5 dpc时细胞外基质编码基因发生显著改变，证明母体重塑异常，并且与子痫前期和子宫内膜异位症等影响生育的疾病相关的术语富集。此外，差异表达基因与通过微阵列鉴定的雌激素受体和表皮生长因子受体调节的基因在方向上重叠。我们的结果表明，Yap1和Wwtr1是哺乳动物成功起始妊娠所必需的。
