The establishment and maintenance of pregnancy requires the coordinated hormonal regulation of corpus luteum (CL) function. Extensive investigations from our laboratory have defined the action and interaction of estradiol (E) and prolactin (PRL) and have led to the recent discovery that PRL signaling through the short form of the PRL receptor (PRLRS) has a severe impact on the ovary, causing follicular degeneration and premature ovarian failure. Because of our observation that the expression of PRLRS in the ovaries of PRL null mice leads to inhibition of Foxo3a and GALT, 2 proteins whose deletion/mutation causes similar premature ovarian failure, we propose in the first specific aim to determine whether PRL acting through PRLRS prevents the expression of Foxo3a which normally stimulates GALT transcriptional activity. Absence of Foxo3 then leads to inhibition of GALT and an increase in galactose and its metabolites, causing galactose toxicity and cell death in granulosa and oocytes. We have also discovered that PRLRS associates with and, when activated by PRL, causes the phosphorylation of a newly discovered enzyme responsible for E synthesis in the CL that we named PRAP/17BHSD-7. This is the first demonstration that direct association of a membrane bound receptor with a steroidogenic enzyme can lead to enzyme phosphorylation. This association may also prevent PRL signaling through PRLRS. The significance of such phosphorylation, and the importance of PRAP/17aHSD-7 in luteal E production, its regulation and its role in the maintenance of pregnancy will be investigated using both cell lines and PRAP/17aHSD-7 null mice that we propose to generate.
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