Analysis of the role of the transcription factor-C/EBPβ in implantation

During early pregnancy, the concerted actions of the maternal steroid hormones, estrogen and progesterone, promote a unique process known as decidualization, which involves extensive proliferation and differentiation of uterine stromal cells. The molecular pathways underlying this hormonally induced cellular transformation, an essential prerequisite for embryo implantation, are poorly understood. We previously identified the transcription factor C/EBPβ as a target of steroid hormone regulation in the uterus. The uteri of C/EBPβ–null mice failed to undergo decidualization, indicating a critical role of this transcription factor in this process. In the present study, analyses of C/EBPβ-null uteri revealed that C/EBPβ mediates the effects of steroid hormones during decidualization in the mouse by modulating the expression of multiple key cell cycle regulatory factors that control the G2-M transition of the proliferating uterine stromal cells. Utilizing a unique primary human endometrial stromal cell (HESC) culture system, in which the cells undergo proliferation and differentiation in response to serum and steroid hormone and cAMP signaling, respectively, my research uncovered that C/EBPβ controls the G1/S transition of the proliferating HESCs by regulating the expression of specific cell cycle regulators such as cyclin E and E2F1. My studies, using a siRNA strategy, revealed that C/EBPβ also plays an essential role in human stromal differentiation. We employed microarray analysis to establish that several factors, such as BMP2, Wnt4, IL11Ra, and STAT3, are downstream targets of C/EBPβ during differentiation of HESCs. Further analysis of IL11Ra-STAT3 signaling and identification of downstream targets of STAT3 suggested that this signal transducer is a critical mediator of the function of C/EBPβ, providing a novel link between C/EBPβ and cytokine signaling pathways that regulate endometrial functions during decidualization. The knowledge gained from this study provides a better understanding of the molecular mechanisms underlying the decidualization phase of implantation. This research also will help us decipher the underlying causes of infertility and recurrent loss of early pregnancy