Molecular mechanisms involved in progesterone receptor regulation of uterine function

Abstract

The ovarian steroid hormone progesterone is a major regulator of uterine function. The actions of this hormone is mediated through its cognate receptor, the progesterone receptor, Pgr. Ablation of the Pgr has shown that this receptor is critical for all female reproductive functions including the ability of the uterus to support and maintain the development of the implanting mouse embryo. High density DNA microarray analysis has identified direct and indirect targets of Pgr action. One of the targets of Pgr action is a member of the Hedgehog morphogen Indian Hedgehog, Ihh. Ihh and members of the Hh signaling cascade show a coordinate expression pattern in the mouse uterus during the preimplantation period of pregnancy. The expression of Ihh and its receptor Patched-1, Ptc1, as well as, down stream targets of Ihh-Ptch1 signaling, such as the orphan nuclear receptor COUP-TF II show that this morphogen pathway mediates communication between the uterine epithelial and stromal compartments. The members of the Ihh signaling axis may function to coordinate the proliferation, vascularization and differentiation of the uterine stroma during pregnancy. This analysis demonstrates that progesterone regulates uterine function in the mouse by coordinating the signals from the uterine epithelium to stroma in the preimplantation mouse uterus.

Figure 1

Mechanisms of Pgr Action. (a) Ligand independent and ligand dependent activation of Pgr (b) Pgr activation of kinase cascades through interaction with Src kinase.

Figure 2

Model of Ihh action mediating epithelial-stromal communication in the uterus.

Figure 3

Quantitative RT-PCR analysis of the expression of Ihh, Ptc and COUP-TF II in pseudopregnany and during an exogenous hormone treatment regimen. Pseudopregnancy: Female mice were mated with vasectomized male mice and collected daily. Presence of the vaginal plug after mating is 0.5dpc. The arrow represents the window of implantation. Endocrine Stimulation of Decidualization: Ovariectomized mice treated with 3 daily injections of 100 ng E2 per mouse. After 2 days rest, mice were then treated with daily injections of 1 mg P4 and 6.7 ng E2 per mouse for 3 days.,s.c. One uterine horn was traumatized by a needle scratch on the anti-mesometrial lumen 6 hrs after the last injection. The contralateral horn was not traumatized and served as a control. Mice were given daily injections of 1mg P4 and 6.7 ng E2 per mouse each day following the trauma, s.c. 6hrs after each injection of 1 mg P4 and 6.7 ng E2, mice were sacrificed and uteri were collected. The arrow represents the time at which the decidual trauma was given.