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Molecular and Cellular Biology, May 2001, p. 3244-3255, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3244-3255.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Control of Spermatogenesis in Mice by the Cyclin D-Dependent Kinase Inhibitors p18Ink4c and p19Ink4d

Frederique Zindy,1 Willem den Besten,1 Bo Chen,2 Jerold E. Rehg,3 Esther Latres,4 Mariano Barbacid,5 Jeffrey W. Pollard,2 Charles J. Sherr,1,6 Paula E. Cohen,2,dagger and Martine F. Roussel1,*

Departments of Tumor Cell Biology1 and Pathology3 and Howard Hughes Medical Institute,6 St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 104612; Department of Pathology, New York University School of Medicine, New York, New York 100164; and Centro Nacional de Investigaciones Oncologicas Carlos III, Majadahonda, 28220 Madrid, Spain5

Received 14 November 2000/Returned for modification 14 December 2000/Accepted 13 February 2001

Male mice lacking both the Ink4c and Ink4d genes, which encode two inhibitors of D-type cyclin-dependent kinases (Cdks), are infertile, whereas female fecundity is unaffected. Both p18Ink4c and p19Ink4d are expressed in the seminiferous tubules of postnatal wild-type mice, being largely confined to postmitotic spermatocytes undergoing meiosis. Their combined loss is associated with the delayed exit of spermatogonia from the mitotic cell cycle, leading to the retarded appearance of meiotic cells that do not properly differentiate and instead undergo apoptosis at an increased frequency. As a result, mice lacking both Ink4c and Ink4d produce few mature sperm, and the residual spermatozoa have reduced motility and decreased viability. Whether or not Ink4d is present, animals lacking Ink4c develop hyperplasia of interstitial testicular Leydig cells, which produce reduced levels of testosterone. The anterior pituitary of fertile mice lacking Ink4c or infertile mice doubly deficient for Ink4c and Ink4d produces normal levels of luteinizing hormone (LH). Therefore, the failure of Leydig cells to produce testosterone is not secondary to defects in LH production, and reduced testosterone levels do not account for infertility in the doubly deficient strain. By contrast, Ink4d-null or double-null mice produce elevated levels of follicle-stimulating hormone (FSH). Because Ink4d-null mice are fertile, increased FSH production by the anterior pituitary is also unlikely to contribute to the sterility observed in Ink4c/Ink4d double-null males. Our data indicate that p18Ink4c and p19Ink4d are essential for male fertility. These two Cdk inhibitors collaborate in regulating spermatogenesis, helping to ensure mitotic exit and the normal meiotic maturation of spermatocytes.

* Corresponding author. Mailing address: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-3481. Fax: (901) 495-2381. E-mail: martine.roussel{at}stjude.org.

dagger Present address: Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461.

Molecular and Cellular Biology, May 2001, p. 3244-3255, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3244-3255.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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