Abstract
Ovulation denotes the discharge of fertilizable oocytes from ovarian follicles. Follicle rupture during ovulation requires extracellular matrix (ECM) degradation at the apex of the follicle. In the teleost medaka, an excellent model for vertebrate ovulation studies, LH-inducible matrix metalloproteinase 15 (Mmp15) plays a critical role during rupture. In this study, we found that follicle ovulation was inhibited not only by roscovitine, the cyclin-dependent protein kinase (CDK) inhibitor, but also by CDK9-inhibitor II, a specific CDK9 inhibitor. Inhibition of follicle ovulation by the inhibitors was accompanied by the suppression of Mmp15 expression in the follicle. In follicles treated with the inhibitors, the formation of the phosphorylated nuclear progestin receptor (Pgr) was inhibited. Roscovitine treatment caused a reduction in the binding of Pgr to the promoter region of mmp15. The expression of Cdk9 and cyclin I (Ccni), and their association in the follicle was demonstrated, suggesting that Cdk9 and Ccni may be involved in the phosphorylation of Pgr in vivo. LH-induced follicular expression of ccni/Ccni was also shown. This study is the first to report the involvement of CDK in ECM degradation during ovulation in a vertebrate species.
Highlights
Vertebrate ovaries represent a vigorously dynamic structure due to the constant change in follicles over time, and such structural changes in the ovaries are closely associated with remodeling of the extracellular matrix (ECM)
In our attempt to search for genes/proteins involved in the expression of mmp15 mRNA, we found that the cyclin-dependent protein kinase (CDK) inhibitor roscovitine inhibited follicle ovulation, and the follicular expression of mmp15 mRNA in the medaka, implicating CDK in the expression of the protease gene in the follicle that is destined to ovulate
Our previous studies using the teleost medaka showed that two distinct proteolytic enzyme systems, the Plau/plasmin system and the MMP system, contribute to follicle rupture
Summary
Vertebrate ovaries represent a vigorously dynamic structure due to the constant change in follicles over time, and such structural changes in the ovaries are closely associated with remodeling of the extracellular matrix (ECM). Our previous studies demonstrated that activation of the plasminogen activator/plasmin (Plau/Plasmin) system and matrix metalloproteinase (Mmp) system is required for the hydrolysis of ECM proteins present in the follicle layers of ovulating follicles [6,7,8,9]. Mmp activated proteolytically by Mmp hydrolyzes type IV collagen, another principal component of the basement membrane, while Mmp degrades the type I collagen most abundantly present in the theca cell layer [6,9] During these hydrolytic processes, plasminogen activator inhibitor-1 [8] and the tissue inhibitor of metalloproteinase-2b (Timp2b) [6] are involved in regulating the Plau/Plasmin system and Mmp system, respectively. We suggest that after phosphorylation, Pgr becomes a functional transcription factor for mmp gene expression, and that Cdk and cyclin I (Ccni) are involved in the process of Pgr phosphorylation
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