CELLULAR SIGNALS IN OVULATION AND LUTEINIZATION

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The luteinizing hormone (LH) surge initiates two processes unique to the vertebrate ovary-ovulation and luteinization. Both require the expression and activation of specific nuclear receptors. PR (progesterone receptor) and SF-1 (steroidogenic factor-1). LH induces the rapid but transient expression of PR mRNA and protein (A and B isoforms) in differentiated granulosa cells of rat preovulatory follicles. Targeted disruption of the PR gene (PRKO) generated mice that do not ovulate, thereby confirming the critical role of PR and granulosa cells in initiating events that control ovulation. The molecular basis by which LH induces PR in granulosa cells remain elusive but appears to involve mechanisms other than or in addition to activation of the estradiol receptor (ER). The availability of the mouse PR promoter and mice deficient in PR provides us with the unique opportunity to extend our studies on the hormonal regulation of PR and to determine the functional roles of PR in the physiology of ovulation. This will be accomplished by 1) analyzing mouse PR promoter-reporter constructs transfected into granulosa cells, 2) using the PRKO mouse model and wildtype mice to identify and analyze the induction of LH and Pr regulated genes and 3) relating the function of these gene products to the activities and localization of specific proteases and kinins likely associated with the ovulatory process. Prior to ovulation, the LH surge initiates the complete molecular reprogramming of granulosa cells leading to their terminal differentiation and the expression of luteal cell specific genes. Our specific genes, alpha2-macroglobulin is regulated by at least two distinct signaling pathways. These include orphan members of the nuclear receptor superfamily, SF-1 and COUP-TFs (chick ovalbumin upstream stimulatory-transcription factors) as well as at least one member of a novel class of transcription factors (signal transducers and activators of transcription or Stats), namely Stat 5b. Whereas the function of SF-1 (COUP-TFs?) can be regulated by gonadotropins in ovarian cells, Stat 5b is activated by PRL. Therefore, we are in the unique position of being able to determine how Stat 5b interacts with orphan nuclear receptors to regulate the expression of alpha2M. These models will allow us to determine how LH regulates the induction (PR) and activation (SF-1) of nuclear transcription factors and how these factors in turn mediate LH stimulation of ovulation and luteinization-two major events in the mammalian ovary that acutely determine fertility.