Regulation of stromal cell decidualization by helix-loop-helix proteins

Brooke K. Compton

Infertility can arise from pregnancy failures early in gestation, around the time of blastocyst implantation. Implantation of the blastocyst into the endometrial lining of the uterus initiates decidualization, or terminal differentiation, of fibroblast-like stromal cells into functional decidual cells critical for early pregnancy. In order to understand and treat early pregnancy loss, it is critical to understand the molecular processes that occur during implantation and decidualization. The helix-loop-helix proteins TCF3, TCF12, and inhibitor of DNA-binding proteins (ID) 1-4 are known to regulate cell differentiation in various tissues. The transcription factors encoded by Tcf3 and Tcf12 are members of the E-box protein family that regulate gene transcription by dimerizing and binding to DNA, while ID1-4 sequester E-proteins and prevent their transcriptional activity. We previously demonstrated in mice that simultaneous conditional ablation of Tcf3 and Tcf12 results in complete infertility. These animals lack normal luteinizing hormone production by the pituitary and display a severely blunted uterine decidual response. The objectives of this study were: 1) to determine the temporal and spatial expression of TCF3, TCF12, and ID1-4 in mouse uterine tissue and human uterine cells in response to sex steroid hormones and early pregnancy, 2) to investigate the infertility phenotype in mice with conditional ablation of Tcf3 and Tcf12, and 3) to analyze fecundity of mice conditionally overexpressing Id4. The data demonstrated that as uterine decidualization within early pregnancy progresses, E-protein expression is amplified while ID expression is attenuated, thus promoting an environment in which cells undergo terminal differentiation. Ablation of Tcf3 and Tcf12 results in significantly higher rates of embryo resorption, disrupted decidualization, and disrupted placentation due to vascular hemorrhaging. These data indicate that Tcf3 and Tcf12 are required for early pregnancy progression. Overexpression of Id4 resulted in a subfertility phenotype; however, the uterine response to artificial decidualization was not impaired. It can be hypothesized that Id4 may be required for folliculogenesis and steroidogenic function within the ovary. The helix-loop-helix proteins Tcf3, Tcf12, and Id1-4 potentially regulate the decidual response during implantation. Disruption to the expression of these proteins could play a role in the high frequency of early pregnancy failures found across mammalian species.

Regulation of stromal cell decidualization by helix-loop-helix proteins

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