Progesterone receptor membrane component 1 in reproductive physiology

Nathaniel Thomas Herrera

doi:10.7273/000004266

Progesterone (P4) is an ovarian-derived female sex steroid hormone that is essential for female reproductive functions and gestation in mammals. Aberrant P4 signaling results in female infertility and has been shown to contribute to several reproductive diseases including endometrial cancer and endometriosis. Many of its actions are mediated by the classical progesterone receptor (PGR), a P4 activated transcription factor that regulates gene expression. While the actions of P4 have been mainly studied through the activation of PGR, recent research has highlighted the importance of two purported non-classical P4 receptors, progesterone receptor membrane component (PGRMC) 1 and PGRMC2. In the female reproductive system, several studies have characterized the expression of PGRMC1 and PGRMC2 during pregnancy and estrous/menstrual cyclicity. Other studies have concluded that PGRMC1 and PGRMC2 function in several cellular reproductive processes. While recent descriptive studies have well-characterized the expression of PGRMC1 and PGRMC2, and several others have found disrupted PGRMC1/2 expression in multiple female reproductive diseases, much less is known about the functional contributions of these genes in fertility. Recent conditional mutagenesis studies from our lab have revealed Pgrmc1 and Pgrmc2 are essential for normal female fertility. To further assess the physiological significance of Pgrmc1 in female fertility, as well as in the male in which essentially nothing is known about PGRMC actions, our lab developed a transgenic mouse that allows for conditional over-expression of PGRMC1. While conditional over-expression of PGRMC1 in the male germ line resulted in an increase in testis weight, as well as a large number of sloughing seminiferous tubules, it did not impact male fertility. In contrast, conditional over-expression of PGRMC1 in the female reproductive system resulted in a severe fertility defect, with a decrease in fecundity as well as the number and size of pups at weaning. Further investigation revealed that conditional over-expression of PGRMC1 impairs post-implantation pre-natal development. Overall, the studies outlined in this thesis are novel due to their utilization of a unique transgenic approach to analyze the physiological significance of PGRMC1 in reproduction.

Progesterone receptor membrane component 1 in reproductive physiology

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