The roles of AKT isoforms in decidualization and embryo implantation using a Progesterone Receptor-Cre mouse model†

Implantation is a complex process requiring a prepared, receptive endometrium, reliant on synchronized decidualization of stromal cells. During this process, cell proliferation and apoptosis are tightly regulated by signaling factors, including the survival and proliferation of the PI3K/AKT pathway. The three AKT isoforms each play distinct physiological roles, but their specific functions in endometrial cell survival and apoptosis remain unclear. We hypothesize that for successful implantation, each AKT isoform has distinct roles in the endometrium during decidualization, which varies throughout the process. To explore this, we developed a unique PGR-Cre tissue-specific mouse model with single and combined knockouts (KO) of each AKT isoform. Using artificial decidualization during pseudopregnancy and normal gestation, we investigated the specific activity of each AKT isoform and their downstream targets to assess the role of AKT pathway. Our results showed that the AKT1-2 KO genotype failed to decidualize during pseudopregnancy and exhibited a reduced number of implantation sites. Interestingly, AKT3 was hyperphosphorylated in the AKT1-2 KO mice and emerged as the primary isoform active throughout decidualization, specifically signaling through GSK3B. This study suggests distinct yet partially redundant roles for AKT1 and AKT2 during decidualization and embryo implantation. We propose that the AKT pathway plays significant role in fertility, and a deeper understanding of its involvement in decidualization could lead to improved strategies for addressing fertility issues. These findings highlight the importance of AKT activity in the cellular and molecular regulation of mouse fertility.