FKBP52-Progesterone Receptor Signaling During Pregnancy

Abstract

The process of implantation absolutely depends on synchronized development of the blastocyst to implantation competency, differentiation of the uterus to the receptive state and a reciprocal dialogue between the blastocyst and the uterus. The uterus is comprised of heterogeneous cell types that respond differentially to ovarian steroid hormones, estrogen and progesterone (P4). P4 is commonly known as the hormone of pregnancy, acting through progesterone receptor (PR) to activate transcription of genes involved in ovulation, uterine receptivity, implantation, decidualization and pregnancy maintenance. However, various aspects of its roles throughout pregnancy are not well understood. Female mice missing Pgr, the gene that encodes PR, are completely infertile with failure of ovulation, fertilization and implantation. This severe phenotype precludes using these null mice to study potential new aspects of P4 function during pregnancy. In contrast, deletion of Fkbp52, a cochaperone for PR, results in uterine-specific P4 resistance, allowing us to address unique aspects of uterine P4-PR signaling during pregnancy. Using Fkbp52 null mice, we first show that while implantation completely fails in these null mice, ovulation, another P4-mediated event, is normal. These results suggest tissue-specific dependence and differential sensitivity of the ovary and uterus to FKBP52-PR mediated P4 action. This study, therefore, provides the first evidence for an in vivo role for FKBP52 in regulating tissue-specific PR and its critical role in uterine receptivity and implantation. We also present evidence that P4-PR-FKBP52 signaling is a function of genetic makeup of mice and is pregnancy stage specific. Collectively, our findings show that FKBP52 deficiency causes uterine P4 resistance during pregnancy, since null females have normal uterine PR and serum P4 levels with reduced PR activity. This work is clinically relevant to genetically diverse populations of women with P4-resistant recurrent pregnancy failure or various gynecological disorders, since there is a correlation between P4 supplementation and decreased risks of recurrent miscarriages and remission of endometriosis.