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Intact Follicular Maturation and Defective Luteal Function in Mice Deficient for Cyclin- Dependent Kinase-4

Departments of Molecular Genetics (D.S.M., S.J., T.T., H.K.), Physiology and Biophysics (D.B.H., G.G.), and Obstetrics and Gynecology (A.T.F.), and Research Resources Center (R.F.), University of Illinois College of Medicine, Chicago, Illinois 60607; Department of Obstetrics and Gynecology (T.T.), Osaka University Medical School, Osaka 565-0871, Japan; National Hormone and Peptide Program (A.F.P.), Harbor-UCLA Medical Center, Research and Education Institute, Torrance, California 90509

Address all correspondence and requests for reprints to: Hiroaki Kiyokawa, M.D., Ph.D., Department of Molecular Genetics, University of Illinois College of Medicine, 900 South Ashland Avenue, M/C 669, Chicago, Illinois 60607-7170. E-mail: kiyokawa{at}uic.edu

Cell cycle progression of granulosa cells is critical for ovarian function, especially follicular maturation. During follicular maturation, FSH induces cyclin D2, which promotes G₁ progression by activating cyclin-dependent kinase-4 (Cdk4). Because cyclin D2-deficient mice exhibit a block in follicular growth, cyclin D2/Cdk4 has been hypothesized to be required for FSH-dependent proliferation of granulosa cells. Here we investigate ovarian function in Cdk4-knockout mice we recently generated. Cdk4^-/- females were sterile, but the morphology of their ovaries appeared normal before sexual maturation. The number of preovulatory follicles and the ovulation efficiency were modestly reduced in gonadotropin-treated Cdk4^-/- mice. However, unlike cyclin D2-deficient mice, Cdk4^-/- mice showed no obvious defect in FSH-induced proliferation of granulosa cells. Cdk4^-/- ovaries displayed normal preovulatory expression of aromatase, PR, and cyclooxygenase-2. Postovulatory progesterone secretion was markedly impaired in Cdk4^-/- mice, although granulosa cells initiated luteinization with induction of p450 side-chain cleavage cytochrome and p27^Kip1. Progesterone treatment rescued implantation and restored fertility in Cdk4^-/- mice. Serum PRL levels after mating were significantly reduced in Cdk4^-/- mice, suggesting the involvement of perturbed PRL regulation in luteal failure. Thus, Cdk4 is critical for luteal function, and some redundant protein(s) can compensate for the absence of Cdk4 in proliferation of granulosa cells.

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