C/EBPβ is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma

Abstract

During early pregnancy, steroid hormones estrogen (E) and progesterone (P) regulate a complex series of interactions between the implanting embryo and the uterus by controlling the proliferation and differentiation of uterine epithelium and stroma in a timely manner. To identify the steroid-regulated genes that control these functions, we performed messenger RNA profiling of mouse uterine tissues at the time of implantation. Our analysis revealed that the expression of the transcription factor CCAAT͞enhancer-binding protein ␤ (C͞EBP␤) is rapidly induced in the pregnant uterus at the time of blastocyst attachment. The expression of C͞EBP␤ increased further during the decidualization phase of pregnancy and was localized in the proliferating as well as the decidualized stromal cells surrounding the implanted embryo. Administration of E or P to ovariectomized females induced C͞EBP␤ expression in both uterine epithelium and stroma, showing a dual regulation of this gene by these hormones. The female C͞EBP␤-null mice are infertile. We, therefore, assessed steroid-hormone-dependent responses in the uteri of these mice. We observed that E-induced proliferation of uterine epithelial cells is markedly compromised in the absence of C͞EBP␤. Most strikingly, there was a complete lack of response of the C͞EBP␤-deficient uteri to an artificial deciduogenic stimulus, indicating a critical role of this transcription factor in regulating the decidualization program. Further analysis revealed defects in steroid-induced stromal cell proliferation and differentiation in C͞EBP␤-null uteri. Collectively, our studies established that C͞EBP␤ is a key mediator of steroid responsiveness of the epithelium and stroma in the mouse uterus.estrogen ͉ progesterone ͉ implantation ͉ decidualization T he physiological functions of the mammalian uterus are profoundly influenced by the concerted actions of steroid hormones estrogen (E) and progesterone (P). Waves of steroidhormone-induced cell proliferation and differentiation dictate the cyclical changes that occur in the uterine epithelium during the reproductive cycle (1-4). During pregnancy, these hormones orchestrate the changes in the uterine epithelium that make it competent to attach to the blastocyst to initiate the process of implantation (1-4). Subsequently, E and P regulate a series of complex interactions between the developing embryo and the cells in the stromal compartment leading to the formation of the decidua, which nourishes the embryo and maintains early pregnancy. Although the details of these events vary in different species, the central roles played by E and P in controlling various phases of early pregnancy are common to many mammals (5).The mouse has served as an important animal model to study the regulation of uterine functions by E and P (6-8). The development of mutant mouse models lacking the estrogen receptor (ER) ␣ and progesterone receptor (PR) has firmly established the requirement of these hormones and their downstream signaling pathways for successful establishmen...

Hmgn1 acts downstream of C/EBPβ to regulate the decidualization of uterine stromal cells in mice

“…Further analysis revealed that the effect of cAMP on Hmgn1 expression was mediated by C/EBPb which was essential for decidualization and controlled the differentiation of stromal cells during decidualization. 14,15 In the uterine stromal cells undergoing decidualization, C/EBPb might induce the expression of Hmgn1. Moreover, overexpression of Hmgn1 could improve the expression of Prl8a2 and Prl3c1 in the C/EBPb siRNA-transfected stromal cells, whereas knockdown of Hmgn1 prevented the C/EBPbinduced up-regulation of Prl8a2 and Prl3c1.…”

“…13,14 Because C/EBPb was also expressed in the decidualized cells and overlapped with Hmgn1, we assumed that there was a relationship between C/EBPb and Hmgn1 during decidualization. To elucidate the relationship, we first studied the regulation of Hmgn1 on C/EBPb.…”

“…[13][14][15] C/EBPb-null uterine stromal cells were unable to undergo proper proliferation and differentiation in response to a decidual stimulation. [14][15][16] Ablation of C/EBPb gene in female mice resulted in infertility with a complete lack of decidual formation.…”

“…[14][15][16] Ablation of C/EBPb gene in female mice resulted in infertility with a complete lack of decidual formation. 2,14 Although it has been proved that C/EBPb might regulate the expression of numerous decidualizationrelated genes, 13 the relationship between C/EBPb and Hmgn1 during decidualization remain poorly understood.…”

Global Analysis of Genes Regulated by HOXA10 in Decidualization Reveals a Role in Cell Proliferation.

“…Over the years, the decidualization process has been studied extensively and the use of transgenic mice has not only demonstrated its necessity for pregnancy but has made it possible to identify critical genes involved in this process. The genes important for decidualization identified thus far include progesterone receptor A (Lydon et al, 1995), homeobox (HOX) A10 (Satokata et al, 1995), cyclooxygenase 2 (Lim et al, 1997), leukemia inhibitory factor (Stewart et al, 1992;Stewart and Cullinan 1997), interleukin 11 receptor (Robb et al, 1998), Hoxa11 (Gendron et al, 1997), FK506 binding protein 4 (Tranguch et al, 2007), CCAAT/enhancer binding protein beta (Mantena et al, 2006), Indian Hedgehog (Lee et al, 2006), steroid receptor coactivator-1 and steroid receptor coactivator-2 and -1 (Mukherjee et al, 2006).…”