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p27^kip1 (Cyclin-Dependent Kinase Inhibitor 1B) Controls Ovarian Development by Suppressing Follicle Endowment and Activation and Promoting Follicle Atresia in Mice

Department of Medical Biochemistry and Biophysics (S.R., P.R., C.D., L.L., K.J., W.T., Y.S., K.L.), Umeå University, SE-901 87 Umeå, Sweden; Qilu Hospital (L.L.), Shandong University, Jinan, 250012 Shandong, China; National Cancer Institute (C.B., P.K.), Mouse Cancer Genetics Program, National Cancer Institute-Frederick, Frederick, Maryland 21702-1201; and Department of Inflammation (S.L.P.), Autoimmunity and Transplantation Research, Roche Palo Alto, LLC, Palo Alto, California 94304

Address all correspondence and requests for reprints to: Kui Liu, Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden. E-mail: kui.liu{at}medchem.umu.se.

In humans, the molecular mechanisms underlying ovarian follicle endowment and activation, which are closely related to the control of female reproduction, occurrence of menopause, and related diseases such as premature ovarian failure, are poorly understood. In the current study, we provide several lines of genetic evidence that the cyclin-dependent kinase (Cdk) inhibitor 1B (commonly known as p27^kip1 or p27) controls ovarian development in mice by suppressing follicle endowment and activation, and by promoting follicle death. In p27-deficient (p27^–/–) mice, postnatal follicle assembly was accelerated, and the number of endowed follicles was doubled as compared with p27^+/+ mice. Moreover, in p27^–/– ovaries the primordial follicle pool was prematurely activated once it was endowed, and at the same time the massive follicular death that occurs before sexual maturity was rescued by loss of p27. In early adulthood, however, the overactivated follicular pool in p27^–/– ovaries was largely depleted, causing premature ovarian failure. Furthermore, we have extensively studied the molecular mechanisms underlying the above-mentioned phenotypes seen in p27^–/– ovaries and have found that p27 controls follicular development by several distinct mechanisms at different stages of development of the ovary. For example, p27 controls oocyte growth by suppressing the functions of Cdk2/Cdc2-cyclin A/E1 in oocytes that are arrested at the diplotene stage of meiosis I. This function of p27 is distinct from its well-known role as a suppressor of cell cycle progression. In addition, we have found that p27 activates the caspase-9-caspase-3-caspase-7-poly (ADP-ribose) polymeraseapoptotic cascade by inhibiting Cdk2/Cdc2-cyclin A/B1 kinase activities in follicles, thereby inducing follicle atresia. Our results suggest that the p27 gene is important in determining mammalian ovarian development. This study therefore provides insight into ovary-borne genetic aberrations that cause defects in folliculogenesis and infertility in humans.

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