Decidualization is critical for favorable uterine receptivity of the blastocyst during implantation and the survival of the embryo. Nevertheless, relatively little is known about the transcription factors and signaling molecules that regulate this vital process. We have demonstrated that human fibroblasts isolated from decidual tissue are precursors of decidual cells and that these cells are an excellent model system to study the regulation of decidualization. Using DNA microarray and RT-PCR analyses, we have identified and categorized many genes not previously known to be regulated during the decidualization process, including the transcription factors Ets-1, fork head in rhabdomyosarcoma (FKHR), Twist, and Id3. We subsequently showed that Ets-1 induces expression of the prolactin gene, which is a specific marker of decidualization; and others recently showed that FKHR induces prolactin gene expression. The overall goal of this proposal is to test the hypothesis that Ets-1, FKHR, Twist and Id3 are critical components of the genetic program that directs human decidualization.
Our specific aims are to test the hypotheses that 1) Ets-I and FKHR, which are up regulated early during decidualization, induce a cascade of transcription factors and signaling molecules that are critical for hormone production and other biochemical processes essential for human decidualization and decidual cell function; 2) Twist and Id3, which are critical for the differentiation of several cell types, are important for maintaining the differentiated state of decidual cells; and 3) the expression of Ets-1, FKHR, Twist and Id3 during decidualization is coordinately regulated by cAMP and Ets-1. The first and second specific aims will utilize experiments with adenoviruses that express the transcription factors as well as antisense oligonucleotides that block their translation.
The third aim will utilize transient transfections, gel shift assays, and site-directed mutagenesis. Since abnormalities of decidualization are frequent causes of spontaneous human abortion, a better understanding of the genetic program involved in decidualization may lead to the development of new drugs that will be useful in the treatment of infertility. The studies should also provide new insight into the mechanisms involved in the induction of prolactin in other extra pituitary tissues (such as lymphocytes and brain) and the genetic programs used by other human progenitor cells during differentiation.
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