In certain mammals (human, rat, mouse) the success of the initial interactions between the embryo and mother depend on uterine stromal cell differentiation (decidualization). In rodents decidualization is a novel two-step process. Stromal cells must first be sensitized by progesterone in order to respond to a subsequent inductive stimulus for differentiation. Thus, unlike other cell systems whose differentiation is initiated by steroid hormones, the hormone itself does not serve as the inducer for decidualization. Preliminary evidence suggests that progesterone acts at the level of cellular transcription to sensitize stromal cells to an inductive stimulus; however, little is known about the cellular and molecular mechanisms through which progesterone regulates sensitivity. To test the hypothesis that progesterone acts at the level of gene expression to engender stromal cell sensitivity, cDNA libraries from sensitized (PX3) and nonsensitized (OVX) uterine stromal (US) and luminal epithelial (UE) cells will be differentially screened to isolate clones derived specifically from progesterone-responsive mRNA. The effects of steroid hormones on the expression of these putative sensitivity messages will be analyzed at the transcriptional and post-transcriptional levels in both US and UE cells to determine how they are regulated in vivo. Antibodies to the protein products of the sensitivity messages will be raised to synthetic peptides derived from the sequenced cDNA. These antibodies will serve to define the regulation and function of these genes in utero. The structure of each sensitivity gene will also be examined to identify regulatory elements and the effects of the gene products on subsequent gene expression will be studied in transfected cells. These studies will expand our understanding of the basic mechanisms which regulate embryo-uterine interactions and may resolve some of the problems related to sterility and fertility that beset animal and human populations.
